CN101227918A - Peptides and peptidomimetics for the treatment of pathologies characterized by inflammatory responses - Google Patents

Abstract

This invention provides novel active agents (e.g. peptides, small organic molecules, amino acid pairs, etc.) peptides that ameliorate one or more symptoms of atherosclerosis and/or other pathologies characterized by an inflammatory response. In certain embodiment, the peptides resemble a G* amphipathic helix of apolipoprotein J. The agents are highly stable and readily administered via an oral route.

Description

Treatment is the peptide and the peptide mimics of the pathology of feature with the inflammatory reaction

[0001] the application requires the USSN60/697 of application on July 7th, 2005, the USSN60/676 of application on April 29th, 495 and 2005, and 431 priority and rights and interests, the content of these two patent documentations all are attached in full by reference and are used for all purposes herein.

Relevant federal government enjoys the statement of invention right in the research and development of subsidizing

[0002] this study portion obtains the support of the state-run heart of NIH, lung, hematopathy institute (Naional Heart Blood Lung Institute of the National Institutesof Health) subsidy HL30568.Federal Government can be enjoyed certain right in the present invention.

Invention field

[0003] the present invention relates to atherosclerosis and reach the field that forms other disease of feature with inflammation and/or various oxidation intermediates (oxidized species).Specifically, the present invention relates to identify and can be taken orally and improve all kinds of activating agents of one or more symptoms that form the disease of feature with inflammatory reaction and/or various oxidation intermediates.

Background of invention

[0004] introducing of inhibin (for example Mevacor , Lipitor  etc.) has made because of heart attack and the mortality rate that causes of apoplexy and has approximately reduced by 1/3rd.Yet heart attack and apoplexy remain death and major cause of morbidity, particularly in the U.S. and the Western European countries.Heart attack and apoplexy are the results who is called as atherosclerotic chronic inflammatory disease.

[0005] cardiovascular disease relate to some causative factors, comprise life style factor, age, hypertension and the hyperlipemias (comprising hypercholesterolemia) such as inherited genetic factors, sex, smoking and diet of disease.Have in these factors several, particularly hyperlipemia is the important risk factor relevant with atherosclerosis with hypercholesterolemia (high blood cholesterol concentration).

[0006] cholesterol is present in the blood as the esterified cholesterol in free cholesterol and the hdl particle (being commonly referred to Chylomicron, very low density lipoprotein (VLDL) (VLDL), low density lipoprotein, LDL (LDL) and high density lipoprotein (HDL)).Total cholesterol concentration in the blood is subjected to following factor affecting: the cholesterol that (1) absorbs from digestive tract, (2) from the diet component synthetic cholesterol of saccharide, protein, fat and ethanol for example, (3) cholesterol that shifts from blood by tissue, particularly liver, cholesterol changes into bile acid, steroid hormone and biliary cholesterol again.

[0007] cholesterolemia concentration keeps the influence that is subjected to two factors of h and E.Inherited genetic factors comprises the concentration of rate-limiting enzyme in the cholesterol biosynthesis, the concentration of the interior low density lipoprotein receptor of liver, concentration, synthesis rate and lipoprotein secretion and the individual sex that the cholesterol bile acid transforms rate-limiting enzyme.The environmental factors that influences blood in human body in cholesterol concentration stable state (hemostasis) comprises the use of diet composition, smoking incidence rate, body movement and various medicines.The diet variable comprises the content of the content of fat and type (satisfied fatty acid and polyunsaturated fatty acid), content of cholesterol, fiber and type, perhaps comprises the content of vitamin (for example vitamin C and vitamin D) and mineral (for example calcium).

[0008] low density lipoprotein, LDL (LDL) oxidation and atherosclerotic pathogenesis height correlation.Have been found that high density lipoprotein (HDL) can protect LDL to make it not oxidized, but find to quicken the LDL oxidation in some cases.The important priming factors of atherosclerosis comprises the generation of the deutero-oxidized phospholipids of LDL.

[0009] in a single day normal HDL has the ability that prevents that these oxidized phospholipids from forming, and forms oxidized phospholipids, also have the ability that makes these oxidized phospholipids inactivations.Yet in some cases, HDL can be transformed into the short scorching molecule that promotes that in fact these oxidized phospholipids form by anti-inflammatory molecular.

[0010] once the someone proposes, and HDL and LDL are as the part innate immune system and work (Navab etc. (2001) Arterioscler.Thromb.Vasc.Biol.21:481-488).Utilize the main protein of simulation HDL, promptly the category-A amphipathic helix peptide of apolipoprotein A-1 (apo A-I) has obtained antiinflammatory HDL (referring to for example WO02/15923).

Summary of the invention

[0011] the invention provides and improve mammiferous angiopathy and/or be the new compositions and the method for one or more symptoms of the disease of feature and/or the disease that forms feature with oxidation activity intermediate (oxidized reactive species) with the inflammatory reaction.This method comprises and gives one or more activating agents of mammal (people that needs are for example arranged) (category-A amphipathic helix peptide for example, some tripeptides, tetrapeptide, pentapeptide and aminoacid are to, some Apo-J (G ^*) peptide and some organic molecule.

[0012] in certain embodiments, the invention provides the peptide that improves the atherosclerosis shape, wherein said peptide comprises the aminoacid sequence or the reverse aminoacid sequence (retro amino acid sequence) of listed peptide in the arbitrary table of table 2-18 (for example table 4, table 5 or table 6 etc.).In certain embodiments, this peptide also comprises with N end or C and holds link coupled protecting group.In certain embodiments, this peptide comprises with N and holds link coupled first protecting group and hold link coupled second protecting group with C.In certain embodiments; protecting group can independently be selected from acetyl group; the alkyl of an amide groups and 3-20 carbon atom; Fmoc; Tboc; 9-fluorenes acetyl group; 1-fluorenes carboxyl; 9-fluorenes carboxyl; 9-Fluorenone-1-carboxyl; benzyloxycarbonyl; xanthyl (Xan); trityl (Trt); 4-methyl trityl (Mtt); 4-methoxyl group trityl (Mmt); 4-methoxyl group-2; 3; 6-trimethyl-benzenesulfonyl (Mtr); -2-sulfonyl (Mts); 4; 4-dimethoxy benzhydryl (Mbh); tosyl (Tos); 2; 2; 5; 7; 8-pentamethyl benzo dihydropyran-6-sulfonyl (Pmc); 4-methyl-benzyl (MeBzl); 4-methoxy-benzyl (MeOBzl); benzyloxy (BzlO); benzyl (Bzl); benzoyl (Bz); 3-nitro-2-pyridine sulfenyl (Npys); 1-(4; 4-dimethyl (dimentyl)-2; 6-dioxo cyclohexylidene (diaxocyclohexylidene)) ethyl (Dde); 2; the 6-dichloro benzyl (2,6-DiCl-Bzl); 2-chlorine benzyloxycarbonyl (2-Cl-Z); 2-bromo-benzyloxy-carbonyl (2-Br-Z); benzyloxymethyl (Bom); tertbutyloxycarbonyl (Boc); cyclohexyloxy (cHxO); tert-butoxy methyl (Bum); tert-butoxy (tBuO); the tert-butyl group (tBu); acetyl group (Ac) and trifluoroacetyl group (TFA).

[0013] in certain embodiments, this peptide comprises with N holds link coupled protecting group, and N end protecting group is to be selected from following protecting group: the alkyl of acetyl group, a propeonyl and 3-20 carbon atom.In certain embodiments, this peptide comprises with C holds link coupled protecting group, and C end protecting group is an amide.In certain embodiments, this peptide comprises: hold link coupled first protecting group with N, wherein this protecting group is to be selected from following protecting group: the alkyl of acetyl group, a propeonyl and 3-20 carbon atom; Hold link coupled second protecting group with C, and C end protecting group is an amide.

[0014] in different embodiments, the one or more aminoacid that comprised in this peptide are " D " aminoacid.In different embodiments, all aminoacid that comprised in this peptide all are " D " aminoacid.This peptide can be chosen wantonly with the pharmacology and go up acceptable mixed with excipients.In certain embodiments, excipient is for being suitable for the mammiferous excipient of orally give.

[0015] in certain embodiments, it is sick and/or be the disease of feature and/or the method that forms the disease of feature with the oxidation activity intermediate with the inflammatory reaction to the invention provides treatment mammal blood vessel.This method generally includes to be enough to improve the consumption of one or more disease symptomses, and one or more activating agents and/or the organic molecule as herein described described in the mammal table 2-18 (for example table 4, table 5 or table 6 etc.) that needs arranged.In certain embodiments, activating agent is to comprise the polypeptide that aminoacid sequence is 4F (SEQ ID NO:5).In certain embodiments, by being selected from following administration: oral administration, nasal-cavity administration, rectally, peritoneal injection, intravascular injection, subcutaneous injection, percutaneous dosing and intramuscular injection.In certain embodiments, activating agent be selected from following medication combined medication: the CETP inhibitor; FTY720; Certican; the DPP4 inhibitor; calcium channel blocker; ApoA1 derivant or analogies or agonist; the PPAR agonist; steroid; imatinib mesylate (Gleevec); cholesterol absorption blocade (Zetia); Vytorin; any renin angiotensin approach blocade; angiotensin ii receptor antagonist (DAIWEN (Diovan) etc.); ACE inhibitor; renin inhibitor; MR antagonist and aldosterone synthase inhibitors; β-blocade; alpha-adrenergic aceptor antagonist; lxr agonist; the FXR agonist; remove receptor B1 agonist; the ABCA1 agonist; adiponectin receptor agonist or adiponectin inducer; stearyl-coenzyme A desaturase I (SCD1) inhibitor; cholesterol synthetic inhibitor (non-inhibin class); Diacrylglycerol acyl transferase I (DGAT1) inhibitor; the acetyl-CoA carboxylase inhibitor 2; the PAI-1 inhibitor; the LP-PLA2 inhibitor; GLP-1; glucokinase activating agents; the CB-1 agonist; AGE inhibitor/clastogen (breaker); pkc inhibitor; antithrombotic drug/coagulant; aspirin; adp receptor blocade (for example clopidogrel (Clopidigrel)); factor Xa inhibitor; the GPIIb/IIIa inhibitor; factor VIIa inhibitors; warfarin; low molecular weight heparin; tissue factor inhibitor; anti-inflammatory drug; probucol and derivant (for example AGI-1067 etc.); the CCR2 antagonist; the CX3CR1 antagonist; the IL-1 antagonist; nitrate and NO donor and phosphodiesterase inhibitor.

[0016] the present invention also provides and comprises table 4, the peptide of the aminoacid sequence of listed peptide or reverse aminoacid sequence is selected from purposes in the following disease in treatment in table 5 or the table 6: atheromatous plaque forms, and atherosclerotic lesion forms, myocardial infarction, apoplexy, congestive heart failure, the arteriole dysfunction, the arteriole disease, aging-related arteriole disease, Alzheimer (Alzheimer ' s disease) dependency arteriole disease, chronic nephropathy dependency arteriole disease, hypertension dependency arteriole disease, multi-infarct dementia dependency arteriole disease, subarachnoid hemorrhage dependency arteriole disease, peripheral blood vessel, chronic obstructive disease of lung (COPD), emphysema, asthma, idiopathic pulmonary fibrosis, pulmonary fibrosis, adult respiratory distress syndrome, osteoporosis, Paget (Paget ' sdisease), coronary artery calcification, rheumatoid arthritis, polyarteritis nodosa, polymyalgia rheumatica, lupus erythematosus, multiple sclerosis, Wegner granulomatosis (Wegener ' sgranulomatosis), central nervous system's vasculitis (CNSV), xerodermosteosis (Sj  gren ' s syndrome), scleroderma, polymyositis, AIDS inflammatory reaction (AIDSinflammatory response), bacterial infection, fungal infection, viral infection, parasitic infection, influenza, bird flu, viral pneumonia, the endotoxin shock syndrome, sepsis, sepsis syndrome, wound/wound, organ transplantation, transplant atherosclerosis, transplant rejection, corneal ulcer, chronic/the disunion wound, ulcerative colitis, reperfusion injury (preventing and/or treating), ischemia reperfusion damage (preventing and/or treating), spinal cord injury (alleviating effect), cancer, myeloma/multiple myeloma, ovarian cancer, breast carcinoma, colon cancer, osteocarcinoma, osteoarthritis, inflammatory bowel, allergic rhinitis, cachexia, diabetes, Alzheimer, implanting prosthetic (implanted prosthesis), biomembrane forms, Crohn disease (Crohns ' disease), dermatitis, acute and chronic eczema, psoriasis, contact dermatitis, scleroderma, type i diabetes, type ii diabetes, teenager disease type diabetes, the prevent diabetes outbreak, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, erection disturbance, degeneration of macula, multiple sclerosis, nephropathy, neuropathy, parkinson disease (Parkinson ' s Disease), peripheral blood vessel and meningitis.

[0017] in another embodiment, the invention provides and comprise table 4, the peptide of the aminoacid sequence of listed peptide or reverse aminoacid sequence is used for the treatment of purposes in the medicine that is selected from following disease in preparation in table 5 or the table 6: atheromatous plaque forms, atherosclerotic lesion forms, myocardial infarction, apoplexy, congestive heart failure, the arteriole dysfunction, the arteriole disease, aging-related arteriole disease, Alzheimer dependency arteriole disease, chronic nephropathy dependency arteriole disease, hypertension dependency arteriole disease, multi-infarct dementia dependency arteriole disease, subarachnoid hemorrhage dependency arteriole disease, peripheral blood vessel, chronic obstructive disease of lung (COPD), emphysema, asthma, idiopathic pulmonary fibrosis, pulmonary fibrosis, adult respiratory distress syndrome, osteoporosis, Paget, coronary artery calcification, rheumatoid arthritis, polyarteritis nodosa, polymyalgia rheumatica, lupus erythematosus, multiple sclerosis, Wegner granulomatosis, central nervous system's vasculitis (CNSV), xerodermosteosis, scleroderma, polymyositis, the AIDS inflammatory reaction, bacterial infection, fungal infection, viral infection, parasitic infection, influenza, bird flu, viral pneumonia, the endotoxin shock syndrome, sepsis, sepsis syndrome, wound/wound, organ transplantation, transplant atherosclerosis, transplant rejection, corneal ulcer, chronic/the disunion wound, ulcerative colitis, reperfusion injury (preventing and/or treating), ischemia reperfusion damage (preventing and/or treating), spinal cord injury (alleviating effect), cancer, myeloma/multiple myeloma, ovarian cancer, breast carcinoma, colon cancer, osteocarcinoma, osteoarthritis, inflammatory bowel, allergic rhinitis, cachexia, diabetes, Alzheimer, implanting prosthetic, biomembrane forms, Crohn disease, dermatitis, acute and chronic eczema, psoriasis, contact dermatitis, scleroderma, type i diabetes, type ii diabetes, teenager disease type diabetes, the prevent diabetes outbreak, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, erection disturbance, degeneration of macula, multiple sclerosis, nephropathy, neuropathy, parkinson disease, peripheral blood vessel and meningitis.

[0018] in certain embodiments, the invention provides be used to deliver a medicament the intraluminal support of body (stent, stent).Support generally includes Support frame (stentframework) and peptide, its middle frame is included in wherein formed a plurality of storages storehouse, and peptide comprises the aminoacid sequence or reverse aminoacid (the retro amino acid) sequence of table 2-18 (for example table 4, table 5 or table 6 etc.) listed peptide and/or its contrary type peptide.In certain embodiments, support comprises and contains peptide that aminoacid sequence is 4F (SEQ ID NO:5) or its contrary type peptide.In certain embodiments, activating agent is included in the polymer.In certain embodiments, Support frame comprises a kind of in metallic substrates (metallic base) or the polymeric substrates (polymeric base).In certain embodiments, the Support frame substrate comprises and is selected from following material: rustless steel, nitinol (nitinol), tantalum, MP35N alloy, platinum, titanium, suitable biocompatible alloy, suitable biocompatible polymer and their combination.In certain embodiments, the storage storehouse that is included in the described support can have micropore (for example about micropore below 20 microns of diameter).In certain embodiments, the diameter range of micropore is about 20 microns to about 50 microns.In different embodiments, about 10 microns to about 50 microns of the depth bounds of micropore.In certain embodiments, micropore spreads all on the entire bracket framework, and Support frame respectively has a perforate on the outer surface of the inner surface of support and support.In different embodiments, support also can comprise the cover layer (cap layer) that is configured on the Support frame inner surface, cover layer wraps up at least a portion in whole hole, and the speed that discharges from Support frame inner surface pharmaceutical polymer for the control medicine provides barrier characteristics.In different embodiments, the storage storehouse comprises along the passage of Support frame outer surface.In different embodiments, polymer comprises ground floor first pharmaceutical polymer with first pharmacy feature, and this polymeric layer comprises second pharmaceutical polymer with second pharmacy feature.In certain embodiments, support also comprises at the barrier layer that contains between the activating agent polymer.In different embodiments, conduit can be connected with Support frame.In certain embodiments, conduit can comprise and is used for the air bag of expandable stent.In certain embodiments, conduit comprises the sheath that withdraws from after the expansion of permission support.

[0019] the present invention also provides the method for making the drug-polymer support.This method generally includes: Support frame is provided; On Support frame, cut out a plurality of storages storehouse; The compositions that will comprise one or more peptides is applied at least one storage storehouse, and described peptide comprises the aminoacid sequence or the reverse aminoacid sequence of listed peptide in arbitrary table of showing 2-18; With composition dries.This method also can comprise dry compositions is applied in the polymeric layer; With the polymer drying.

[0020] the present invention also provides the method for treatment angiopathy.This method comprises in the aforesaid support implanting to human body lumen of vessels; Expandable stent; At least a activating agent (for example showing the activating agent in the arbitrary table of 2-18) is discharged from least one surface of support.

[0021] in certain embodiments, the present invention forecloses described one or more peptides of following document clearly: U.S. Patent number: 6,037,323,4,643,988,6,933,279,6,930,085,6,664,230,3,767,040,6,037,323; United States Patent (USP) publication: 2005/0164950,2004/0266671,2004/0254120,2004/0057871,2003/0229015,2003/0191057,2003/0171277,2003/0045460,2003/0040505; PCT publication No. WO 2002/15923, WO 1999/16408, WO1997/36927; And/or (1992) Arteriosclerosis and Thrombosis such as Garber, 12:886-894, the content of these documents all is attached to herein by reference.

Definition

[0022] term " treatment " is when being used to refer to when for example treating pathology or disease, be meant one or more symptoms that alleviate and/or eliminate this pathology or disease, and/or reduce one or more paresthesia epilepsy speed or orders of severity of this pathology or disease, and/or prevent this pathology or disease.

[0023] term " separate () ", " purification () " or " biologically pure " when relating to isolating polypeptide, be meant the component that normally accompanies when material does not contain its native state basically or in essence and exists with it.As for nucleic acid and/or polypeptide, this term can refer to nucleic acid or the polypeptide that flank no longer is connected with the common sequence of adjacency with it under the natural situation.The polypeptide of chemosynthesis is " isolating ", because they are not present in native state (for example blood, serum etc.).In certain embodiments, term " isolating " is meant natural non-existent polypeptide.

[0024] term " polypeptide ", " peptide " and " protein " are used interchangeably herein, are meant the polymer of amino acid residue.This term is applicable to the aminoacid polymer, and wherein one or more amino acid residues are corresponding naturally occurring aminoacid and the polymeric artificial chemical analog of naturally occurring aminoacid.

[0025] term " amphipathic helix peptide " is meant the peptide that comprises at least one amphipathic helix (amphipathic helix territory (amphipathic helical domain)).Some amphipathic helix peptide of the present invention can comprise two or more (for example 3,4,5 ...) amphipathic helixs.

[0026] term " category-A amphipathic helix " is meant the protein structure of the alpha-helix that forms polarization face and non-polar plane separation, wherein positively charged residue is present in the interface of polar-nonpolar, electronegative residue then is present in the center of polar surface (referring to (1990) Proteins:Structure such as for example Segrest, Function, and Genetics 8:103-117).

[0027] known " apolipoprotein J " (apo J) has multiple title, comprise that a bunch albumen, TRPM2, GP80 and SP40 are (referring to for example Fritz (1995), the 112nd page: Clusterin:Role in Vertebrate Development, Function, and Adaptation (bunch albumen: the effect in vertebrates growth, function and adaptation) (Harmony JAK Ed.), R.G.Landes, Georgetown, TX).Be described as cultivating the heterodimer glycoprotein and the secretory protein component (referring to (1982) Biol.Reprod.27:233240 such as for example Kissinger) of rat sustenticular cell (Sertoli cell) first.Translation product is the strand precursor protein, through being cut into 34kDa α subunit and the 47kDa β subunit (referring to for example Collard and Griswold (1987) Biochem.26:3297-3303) that disulfide bond connects in the born of the same parents.Apolipoprotein J and cell injury, lipid transfer, apoptosis-related, it can participate in removing the cell debris that is produced by cell injury or cell death.Show that bunch albumen is with high-affinity combine with the multiple molecule that comprises lipid, peptide and protein and hydrophobic probe 1-anilino--8-naphthalene sulfonate (Bailey etc. (2001) Biochem.40:11828-11840).

[0028] G class amphipathic helix is present in the globular protein, so called after G class.The feature of this class amphipathic helix is that positively charged residue and electronegative residue are randomly dispersed on the polar surface of narrow non-polar plane.Because narrow non-polar plane, this class are difficult for associating (referring to (1990) Proteins:Structure such as for example Segrest, Function, and Genetics.8:103-117 with phospholipid; Erratum (1991) Proteins:Structure, Function and Genetics, 9:79).Some tradable apolipoproteins have the feature similar but inequality to the G amphipathic helix.Similar with G class amphipathic helix, this class has the positively charged residue of random distribution and electronegative residue on polar surface.Yet opposite with the G class amphipathic helix with narrow non-polar plane, this class has roomy non-polar plane, allows such easy and phospholipids incorporate, and such is named as G ^*The class amphipathic helix is to be different from G class amphipathic helix (referring to (1992) J.Lipid Res.33:141-166 such as for example Segrest; Anantharamaiah etc. (1993), the 109-142 page or leaf: The AmphipathicHelix, Epand, the R.M. chief editor, CRC Press, Boca Raton, Florida).To the amphipathic helix territory identify and the computer program of classifying referring to (1992) J.Lipid Res.33:287-296 such as Jones), include but not limited to helical wheel program (helical wheel program) (WHEEL or WHEEL/SNORKEL), spiral net program (helical net program) (HELNET, HELNET/SNORKEL, HELNET/Angle), helical wheel appendage (program for addition of helical wheel) (COMBO or COMBO/SNORKEL), spiral net appendage (program for addition of helicalnet) (COMNET, COMNET/SNORKEL, COMBO/SELECT, COMBO/NET), total wheel program (consensus wheel program) (CONSENSUS, CONSENSUS/SNORKEL) etc.

[0029] term " improvement " is when being used for " improving atherosclerotic one or more symptoms ", and being meant minimizing, prevention or eliminating with atherosclerosis and/or related pathologies is one or more symptoms of feature.This minimizing include but not limited to the minimizing that the reducing or eliminating of oxidized phospholipids, atheromatous plaque form and break, for example heart attack of clinical setting, angina pectoris or apoplexy reduces, hypertension reduces, the inflammatory protein biosynthesis reduces, plasma cholesterol reduces, or the like.

[0030] term " enantiomer aminoacid (enantiomeric amino acid) " be meant can at least 2 kinds the aminoacid that exists of non-superimposable mirror image form each other.Most of aminoacid (except the glycine) all are enantiomer, have so-called L type (L aminoacid) or D type (D aminoacid).Most of naturally occurring aminoacid are " L " aminoacid.Term " D aminoacid " and " L aminoacid " are used to refer to amino acid whose absolute configuration, rather than the concrete direction of rotation of linearly polarized light.This paper usage is consistent with those skilled in the art's normal usage.This paper is with standard single-letter or trigram code name aminoacid, as the ST.25 standard of industrial property information and document handbook (Handbook On Industrial Property Information and Documentation) regulation.

[0031] term " protecting group " is meant when sealing or shelter the chemical group of this functional group's character when being connected with amino acid whose functional group (for example side chain, α amino, α carboxyl etc.).Preferred N end protecting group includes but not limited to acetyl group or amino.Other N end protecting group includes but not limited to alkyl chain, propeonyl, formoxyl and other group as fatty acid.Preferred C end protecting group includes but not limited to form the group of amide or ester.

[0032] " protection phospholipid makes its not oxidized dose of oxidation "; be meant that chemical compound reduces the ability of phospholipid oxidation speed (the perhaps amount of the oxidized phospholipids that produces) when phospholipid and oxidant (for example hydrogen peroxide, 13-(S)-HPODE, 15-(S)-HPETE, HPODE, HPETE, HODE, HETE etc.) when contacting.

[0033] term " low density lipoprotein, LDL " or " LDL " are according to the conventional usage definition of those skilled in the art.In general, LDL is meant that when separating with ultracentrifugation density range is lipid-protein complex of d=1.019 to d=1.063.

[0034] term " high density lipoprotein " or " HDL " are according to the conventional usage definition of those skilled in the art.In general, " HDL " is meant when separating with ultracentrifugation, and density range is lipid-protein complex of d=1.063 to d=1.21.

[0035] term " I organizes HDL " is to instigate lipid oxide (for example in low density lipoprotein, LDL) reduction or protection lipid oxide to make high density lipoprotein or its component (for example apo A-I, paraoxonase, platelet activating factor PAF-AH etc.) of its not oxidized dose of oxidation.

[0036] term " II organizes HDL " is meant at the protection lipid and makes it not oxidized or when repairing (for example reduction) lipid oxide, the active reduction or the HDL of non-activity.

[0037] term " HDL component " is meant the component (for example molecule) that comprises high density lipoprotein (HDL).Be used to protect lipid to make its mensuration not oxidized or that repair the HDL of (for example making the lipid oxide reduction) also comprise the mensuration of this active HDL component of performance (for example apo A-I, paraoxonase, platelet activating factor PAF-AH etc.).

[0038] term " people apo A-I peptide " is meant the total length people apo A-I peptide or its fragment or the domain that comprise the category-A amphipathic helix.

[0039] " mononuclear cell reacts (monocytic reaction) " used herein is meant the monocytic activity feature that forms relevant " inflammatory reaction " with atheromatous plaque.The feature of mononuclear cell reaction is that monocyte adhesion is divided into macrophage to last and/or deeply interior subcutaneous spatial chemotaxis of the cell (for example vascular endothelial cell) of blood vessel wall and/or mononuclear cell.

[0040] term " lacks and changes " when relating to the amount of oxidized phospholipids, be meant to lack detectable variation, more preferably lack significant change on the statistics (for example confidence level is at least 85%, preferably at least 90%, more preferably at least 95%, most preferably at least 98% or 99%).Lack detectable variation and can also be meant that the oxidized phospholipids level changes when measuring, but the variation of shortage protein not as described herein or relevant other positive control or negative control is big.

[0041] this paper can use following abbreviation: PAPC:L-α-1-palmityl-2-arachidonic acyl-sn-glyceryl-3-phosphocholine; POVPC:1-palmityl-2-(5-oxo valeryl)-sn-glyceryl-3-phosphocholine; PGPC:1-palmityl-2-glutaryl-sn-glyceryl-3-phosphocholine; PEIPC:1-palmityl-2-(5, the different prostaglandin of 6-epoxy (isoprostane) E2)-sn-glyceryl-3-phosphocholine; ChC18:2: linoleic acid cholesterol ester; ChC18:2-OOH: hydroperoxylinoleic acid cholesterol ester; DMPC:1, the two myristoyls of 2--rac-glyceryl-3-phosphocholine; PON: paraoxonase; HPF: standard high power field; PAPC:L-α-1-palmityl-2-arachidonic acyl-sn-glyceryl-3-phosphocholine; BL/6:C57BL/6J; C3H:C3H/HeJ.

[0042] term " the conservative replacement " is to be used to refer to activity (specificity (for example for lipoprotein)) or the binding affinity (for example for lipid or lipoprotein) that does not change molecule in protein or the peptide behind the aminoacid replacement basically).Usually, conserved amino acid replaces and comprises that an aminoacid is replaced by the aminoacid that another has similar chemical property (for example electric charge or hydrophobicity).Following 6 groups respectively comprise the typical conservative each other aminoacid that replaces: 1) alanine (A), serine (S), threonine (T); 2) aspartic acid (D), glutamic acid (E); 3) agedoite (N), glutamine (Q); 4) arginine (R), lysine (K); 5) isoleucine (I), leucine (L), methionine (M), valine (V); With 6) phenylalanine (F), tyrosine (Y), tryptophan (W).

[0043] in two or more nucleotide sequences of this paper or peptide sequence, term " identical " or " homogeneity " percentage ratio are meant when when carrying out maximum correspondence comparison and comparison, identical two or more sequences or subsequence or identical amino acid residue or nucleotide with particular percentile, as use following sequence comparison algorithm or by range estimation surveyed.As for peptide of the present invention, sequence homogeneity is to determine with the total length of peptide.

[0044] relatively, a common sequence is as reference sequence, with sequence to be measured by comparison for sequence.When the utilization sequence comparison algorithm, with sequence to be measured and reference sequence input computer, if needed, specify the subsequence coordinate, and specified sequence algorithm routine parameter.According to specified program parameter, sequence comparison algorithm calculates the sequence homogeneity percentage ratio of sequence to be measured with respect to reference sequence then.

[0045] can pass through following algorithm, carry out the best comparison of sequence and be used for comparison, for example local homology's algorithm (Smith﹠amp; Waterman, Adv.Appl.Math.2:482 (1981), homology alignment algorithm (Needleman﹠amp; Wunsch, J.Mol.Biol.48:443 (1970), similarity retrieval method (Pearson﹠amp; Lipman (1988) Proc.Natl.Acad.Sci.USA85:2444), computerized computing (GAP, BESTFIT, FASTA and the TFASTA of these algorithms, Wisconsin Genetics Software Package, Genetics ComputerGroup, 575 Science Dr.Madison, WI) or by visual inspection (generally referring to Ausubel etc., ibid).

[0046] useful algorithm example is PILEUP.PILEUP uses asymptotic matched sequence comparison, creates the multisequencing comparison by one group of correlated series, to show dependency and sequence homogeneity percentage ratio.Also draw dendrogram or dendogram and show bunch sibship that is used to create sequence alignment.PILEUP adopts Feng and Doolittle (1987), the method for simplifying of the asymptotic sequence alignment method of J.Mol.Evol.35:351-360.Employed method is similar to Higgins and Sharp (1989), the method that CABIOS 5:151-153 describes.Described program can be compared nearly 300 sequences, and each sequence greatest length is 5,000 nucleotide or aminoacid.Described multisequencing comparison method starts from two pairing comparisons of similar sequences the most, produces one group two sequences through comparison.This group sequence and next maximally related sequence or next group are compared through the sequence of comparison then.By the simple extension that the pairing of two indivedual sequences is compared, two groups of sequences are compared.By a series of asymptotic matched sequence comparisons, finish final sequence alignment.By aminoacid or the nucleotide coordinate and the designated program parameter of specifying concrete sequence and sequence thereof relatively to distinguish, move this program.For example, adopt following parameter: the terminal room (weighted end gap) of default room weighting (default gap weight) (3.00), default room length weighting (default gaplength weight) (0.10) and weighting, reference sequence and other sequence to be measured can be compared, to determine that sequence homogeneity concerns percentage ratio.

[0047] is applicable to that another algorithm examples of measuring sequence homogeneity and sequence similarity percentage ratio is the BLAST algorithm, referring to (1990) J.Mol.Biol.215:403-410 such as Altschul.The public can pass through the National Center for Biotechnology Information ( Http:// www.ncbi.nlm.nih.gov/) obtain to be used to carry out the software that BLAST analyzes.This algorithm comprises the short word string that at first is tested and appraised length W in search sequence, the word string of equal length when comparison or coupling or satisfy some positive threshold scores T in this word string and the database sequence, thus identify high sub-sequence pairing (HSP).T is called as contiguous word string threshold value (Altschul etc., ibid).These original contiguous word strings are hit the seed that contains their longer HSP as initial search with discovery.As long as accumulated sequence comparison score value can increase, word string is hit then and is extended along each sequence with both direction.For nucleotide sequence, operation parameter M (the prize branch of a pair of coupling residue (reward score); Always＞0) and the N (point penalty of mispairing residue (penalty score); Always＜0), calculate the accumulation score value.For aminoacid sequence, use the marking matrix to calculate the accumulation score value.The extension that word string is hit in each direction stops when running into one of following situation: accumulated sequence comparison score value is than the low quantity X of maximum of its acquisition; The accumulation score value is below zero or zero, and this is because due to the accumulation of one or more negative marking residue comparisons; Perhaps arrive the end of arbitrary sequence.BLAST algorithm parameter W, T and X determine the sensitivity and the speed of described comparison.The default word length (wordlength) that BLASTN program (being used for nucleotide sequence) is used is 11 (W), and expected value (expectation) is 10 (E), M=5, and N=-4, and compare two chains.For aminoacid sequence, the default word length (W) that the BLASTP program is used is 3, and expected value (E) is 10, uses BLOSUM62 marking matrix (referring to Henikoff and Henikoff (1989) Proc.Natl.Acad.Sci.U.S.A.89:10915).

[0048] except that sequence of calculation homogeneity percentage ratio, the BLAST algorithm also carries out the statistical analysis of similarity between two sequences (referring to for example Karlin﹠amp; Altschul (1993) Proc.Natl.Acad.Sci.USA, 90:5873-5787).It is minimum and probability (P (N)) that a kind of similarity that the BLAST algorithm provides is measured, and it provides the index of the probability that two nucleotide sequences or aminoacid sequence may mate accidentally.For example, if determined nucleic acid and reference nucleic acid in relatively minimum and probability approximately less than 0.1, more preferably approximately less than 0.01,, think that then determined nucleic acid is similar to reference sequence most preferably approximately less than 0.001.

[0049] term " with ... coupling " is when being used to relate to when using one or more medicines and one or more activating agent couplings as herein described, is meant to give medicine and activating agent makes it have at least some overlapping in time on the physiologically active to organism.Therefore, medicine and activating agent can while and/or sequential giving.During sequential giving, before giving second portion, certain actual delay (for example a few minutes or even a few hours or a couple of days) may even be arranged, as long as when for the second time institute gives the medicine administration or when activity occurring in vivo, the first time, administered agents/activating agent made organism produce some physiological change.

[0050] term " closer to each other in peptide spiral colyliform figure (helical wheel diagram) " or " contiguous in peptide spiral colyliform figure " are when relating to the residue of helical peptides, be meant that residue seems approaching or contiguous in spiral colyliform figure, even may and keep off in the linear peptides or vicinity.For example, residue " A, E, K, W, K and F " is contiguous in spiral colyliform figure shown in Figure 15, even these residues are not contiguous in linear peptides.

The accompanying drawing summary

[0051] Fig. 1 is illustrated in and hatches altogether in the experiment, and (Navab etc. (2002) Circulation is 105:290-292) with by the apo-J peptide 336 (D-J336 of D aminoacid preparation for D4F ^*) to the comparison of the active effect of the inductive monocyte chemotactic of vitro inhibition LDL.Data are meansigma methods ± SD of the mononuclear cell number of 9 interior migrations of high power field in the culture (in quadruplicate).(D-J336＝Ac-LLEQLNEQFNWVSRLANLTQGE-NH ₂，SEQ ID NO：1)。

[0052] Fig. 2 represents to compare with D-4F, and arterial wall cell uses the D-J336 pretreatment to the active inhibition of the inductive monocyte chemotactic of LDL.Data are meansigma methods ± SD of the mononuclear cell number of 9 interior migrations of high power field in the culture (in quadruplicate).

[0053] Fig. 3 represents the effect to the HDL protective capability in the ldl receptor nude mouse of apo J peptide mimics.Numerical value is the meansigma methods ± SD that measures the mononuclear cell number that moves in 9 high power fields in every hole in the hole (in quadruplicate).

[0054] Fig. 4 is illustrated in the apo E nude mouse that gives oral peptide, and HDL prevents the inductive monocyte chemotactic activity of LDL.Numerical value is the meansigma methods ± SD that measures the mononuclear cell number that moves in 9 high power fields in every hole in the hole (in quadruplicate).Significant difference p＜0.05 compared with no peptide mHDL represented in asterisk).

[0055] Fig. 5 represents the effect to the LDL oxidation sensitive of oral apo A-1 peptide mimics and apoJ peptide.Numerical value is the meansigma methods ± SD that measures the mononuclear cell number that moves in 9 high power fields in every hole in the hole (in quadruplicate).The significant difference (p＜0.05) compared with no peptide LDL represented in asterisk.

[0056] Fig. 6 represents the effect to the HDL protective capability of oral apoA-1 peptide mimics and apoJ peptide.Numerical value is the meansigma methods ± SD that measures the mononuclear cell number that moves in 9 high power fields in every hole in the hole (in quadruplicate).The significant difference (p＜0.05) compared with no peptide mHDL represented in asterisk.

[0057] Fig. 7 represents that oral apoA-1 peptide mimics and apoJ peptide are to the active effect of blood plasma paraoxonase.Numerical value is the meansigma methods ± SD of five equilibrium blood plasma (in quadruplicate) reading.Asterisk is represented to contrast the significant difference (p＜0.05) that blood plasma is compared with no peptide.

[0058] Fig. 8 represent apoE-/-the oral G of mice ^*Peptide is to the effect of HDL protective capability.Numerical value is the meansigma methods ± SD of five equilibrium blood plasma (in quadruplicate) reading.Asterisk is represented to contrast the significant difference (p＜0.05) that blood plasma is compared with no peptide.

[0059] Fig. 9 represent ApoE-/-the oral G of mice ^*Peptide 146-156 is to the effect of HDL protective capability.

[0060] Figure 10 A to Figure 10 C represents the spiral colyliform figure of some peptide of the present invention.Figure 10 A:V ²W ³A ⁵F ^10,17-D-4F; Figure 10 B:W ³-D-4F; Figure 10 C:V ²W ³F ¹⁰-D-4F.

[0061] Figure 11 A. joins normal man LDL (LDL) in human artery's wall coculture with following composition: do not contain people HDL (not adding), perhaps contain people HDL (+contrast HDL), perhaps contain and derive from the mice HDL (+Chow HDL) that gives the mice pellet apoE nude mouse that (Chow) spends the night, perhaps contain the mice HDL (+D4F HDL) that derives from the apoE nude mouse that interpolation D-4F spends the night in the mice pellet, perhaps contain derive from the mice HDL that gives in the mice pellet to add the apoE nude mouse that G5-D-4F spends the night (+G5HDL), perhaps contain to derive from and give to add G5 in the mice pellet, the mice HDL of the apoE nude mouse that 10-D-4F spends the night (+5-10HDL), perhaps contain to derive from and give to add G5 in the mice pellet, the mice HDL of the apoE nude mouse that 11-D-4F spends the night (+5-11HDL), according to previous described method measure the monocytic chemotactic activity of gained (Navab etc. (2002) Circulation, 105:290-292).

[0062] Figure 12 represents that peptide of the present invention is effective to alleviating diabetic symptom (for example blood glucose).Give fat Zucker rat blood-letting in 26 ages in week, peritoneal injection D-4F every day (5.0mg/kg/ days) treats then.Give the rat blood-letting after 10 days once more, measure plasma glucose and lipid hydroperoxide (LOOH). ^*p＝0.027； ^**p＝0.0017。

[0063] Figure 13. give fat Zucker rat injection D-4F (5mg/kg/ days) week in 16 ages in week, make rat experience common carotid artery balloon injured simultaneously.After 2 weeks, put to death rat, measure the ratio of film in the inner membrance.

[0064] Figure 14 shows in apo E nude mouse, and the product that solution is combined to flow process is very high to producing the HDL and preceding β HDL (pre-betaHDL) biological activity that suppress the inductive monocyte chemotaxis of LDL.Give ApoE nude mouse feed 5 micrograms such as the synthetic D-4F of above-mentioned method (Frgmnt), perhaps give the mice pellet (Chow) that does not contain D-4F of mice equivalent.Fed back 12 hours, and gave the mice blood-letting, its blood plasma FPLC fractionated.LDL (100 microgram LDL-cholesterol) is joined in the human artery parietal cell coculture with following compositions: human artery parietal cell (LDL) or contrast people HDL (contrast HDL) or HDL (50 microgram HDL-cholesterol) are only arranged or supply with D-4F (Frgmnt) or do not supply with the mice post-HDL (pHDL of D-4F (Chow); Preceding β HDL), measure the monocyte chemotactic activity that is produced.

[0065] Figure 15 represents the spiral colyliform figure of 4F and reverse (reverse) (reverse (retro)) 4F.Oppositely 4F (reverse-4F) is the mirror image of 4F, and aminoacid relative position and hydrophilic surface to each other is identical with hydrophobic surface.

[0066] Figure 16 represents D-4F and the oppositely comparison of the HDL inflammation index of D-4F.

Detailed Description Of The Invention

I. methods for the treatment of

[0067] activating agent described herein (for example peptide, organic molecule, the amino acid equity) AR and/or the order of severity that are effective to alleviate one or more symptoms of one or more indications described herein and/or reduce one or more indications described herein. Specifically, activating agent described herein (for example peptide, organic molecule, amino acid equity) is effective to alleviate atherosclerotic one or more symptoms. In the situation that is not subjected to the particular theory constraint, we think that peptide and short scorching oxidized phospholipids (for example Ox-PAPC, POVPC, PGPC and PEIPC) form necessary " seeding molecule (seeding molecule) " combination.

[0068] in addition, because many inflammatory diseases and/or other pathology are at least part of by the lipid oxide mediation, so we think that peptide of the present invention is effective to the disease that forms feature of improving with the biologically active lipid oxide. In addition, also have many Other diseases to it seems it is effective for activating agent described herein.

[0069] introduces below for activating agent described herein and it seems it is the tool property alleviated and/or preventative a lot of pathology.

A) atherosclerotic and related pathologies

[0070] we find that normal HDL suppresses 3 steps that mild oxidation LDL forms. Specifically, we confirm can remove and remove the seeding molecule from the LDL that comprises HPODE and HPETE with apo A-I or apo A-I simulating peptide (37pA) extracorporeal treatment people LDL. These seeding molecules are that human artery parietal cell coculture can oxidation LDL and to induce arterial wall cell to produce the monocyte chemotactic activity for LDL necessary. We also confirm the A-I to injected in mice apo, after perhaps giving people's infusion, the oxidation of the anti-human artery parietal cell of LDL that separates in injection or the mouse of infusion apo A-I or the people volunteer's body can not induced the monocyte chemotactic activity in the arterial wall cell coculture.

[0071] defencive function of the various activating agents of the present invention is referring to patent application (09/645 of application on August 24th, 2000; 454,09/896 of application on June 29 calendar year 2001; the WO 02/15923 (PCT/US01/26497) of on June 29th, 841 and 2001 application is referring to the Fig. 1-5 among the WO 02/15923 for example. The figure A of Fig. 1, figure B, figure C and figure D show among the WO 02/15923, in the ApoE nude mouse¹⁴The association of C-D-5F and blood constitutent. Also proof derives from the HDL that feeds atherogenic diet and injection PBS mouse, can not suppress the oxidation of people LDL in human artery's wall is cultivated altogether, can not suppress the monocyte chemotactic activity that LDL induces. By contrast, derive from and feed atherogenic diet and inject the HDL of the mouse of peptide described herein every day, when inhibition people LDL oxidation is active with the monocyte chemotactic that stops LDL to induce in coculture the same with normal person HDL effective (Fig. 2 A among the WO 02/15923 and Fig. 2 B). In addition, inject the LDL that extracts the PBS mouse from feed atherogenic diet and every day, than from feeding same diet but inject the easier oxidation of LDL that the mouse of 20 μ g 5F peptides is extracted, the easier monocyte chemotactic activity of inducing every day. Immunogenicity (Fig. 4 among the WO 02/15923) can not appear in the D peptide.

[0072] the human artery parietal cell is to deriving from feed atherogenic diet and the HDL of the mouse of injection peptide of the present invention and the vitro reactions of LDL, and the Protective effect shown with this peptide is consistent. Although the level of T-CHOL, LDL-cholesterol, IDL+VLDL-cholesterol is similar, it is lower that the HDL-cholesterol accounts for T-CHOL percentage, and the pathology score value of the animal of still feed atherogenic diet and injection peptide is lower (Fig. 5 among the WO 02/15923) obviously. Therefore, the peptide of the present invention process of atherogenic diet mouse atherosclerotic lesion that suppresses to feed.

[0073] therefore, in one embodiment, the present invention is by giving one or more activating agents described herein, is provided for improving and/or the method for one or more symptoms that prevention of arterial is atherosis.

It is also noted that [0074] c-reactive protein (markers of inflammation) raises in congestive heart failure. Equally, in the congestive heart failure, there are reactive oxygen intermediate accumulation and angiokinesis unusual. Because activating agent described herein in the various oxidation intermediates of prevention/reduce form effect and/or because they are improving effect (vide infra) in vascular reactivity (vasoreactivity) and/or the arteriole function, so activating agent described herein can be effective to treat congestive heart failure.

B) arteriole/blood vessel indication

[0075] ratio that thickens even the minimum also little blood vessel (being arteriole) of artery, the generating function obstacle causes the damage of Various Tissues such as brain and kidney of end-organ. It is believed that activating agent described herein can work to improve the arteriole 26S Proteasome Structure and Function and/or slow down the handicapped speed of arteriole and/or the order of severity. In the situation that is not subjected to the particular theory constraint, we think that the arteriole dysfunction is the cause of disease of various encephalopathics and ephrosis. Use activating agent as herein described, therefore the method for improving arteriole 26S Proteasome Structure and Function and protection end-organ (for example brain and kidney) function can be provided.

[0076] for example, give one or more activating agents described herein, expection can reduce one or more symptoms of following disease or slow down outbreak or the order of severity of these diseases: aging-related arteriole disease and/or Alzheimer disease and/or Parkinson's and/or multi-infarct dementia and/or subarachnoid hemorrhage etc. Similarly, give one or more activating agents described herein, expection can alleviate chronic kidney disease and/or hypertensive one or more symptoms and/or slow down chronic kidney disease and/or hypertensive outbreak and/or the order of severity.

[0077] similarly, activating agent demonstration described herein can improve vascular reactivity. Because vascular reactivity and/or arteriole function improve, so activating agent described herein is applicable to the diseases such as treatment peripheral artery disease, erectile dysfunction.

C) lung indication

[0078] activating agent described herein also is applicable to the various lung indications for the treatment of. These indications include but not limited to chronic obstructive disease of lung (COPD), pulmonary emphysema, tuberculosis, asthma, idiopathic pulmonary fibrosis etc.

D) alleviate CAC and osteoporosis related symptoms or disease

[0079] usually there are (Ouchi etc. (1993) Ann NY Acad Sci.676:297-307 simultaneously in angiosteosis and osteoporosis with the title disease; Boukhris and Becker (1972) JAMA, 219:1307-1311; Banks etc. (1994) Eur J Clin Invest.24:813-817; Laroche etc. (1994) Clin Rheumatol.13:611-614; Broulik and Kapitola (1993) Endocr Regul.27:57-60; Frye etc. (1992) Bone Mine.19:185-194; Barengolts etc. (1998) Calcif Tissue Int.62:209-213; Burnett and Vasikaran (2002) Ann Clin Biochem.39:203-210). The people such as Parhami (Parhami etc. (1997) Arterioscl Thromb Vasc Biol.17:680-687) show, the biologically active lipid among the LDL of mild oxidation (MM-LDL) and the MM-LDL [be the 1-palmityl-2-arachidonic acyl-sn-glyceryl-3-phosphocholine of oxidation) (Ox-PAPC)] and Chinese mugwort rope Epstein (isoprostane), the different PGE of 8-₂, rather than not oxidized phospholipids (PAPC) or Chinese mugwort rope Epstein 8-different PGF_2αThe osteoblast differentiation of external evoked alkaline phosphatase activities and calcification vascular cell (CVC), but suppress the differentiation of MC3T3-E1 osteocyte.

[0080] osteon is similar to arterial wall, because osteon is positioned at the inner chamber central authorities that are arranged in by endothelial cell that centered on by subcutaneous space, matrix and fibroblast-like cells are contained in interior subcutaneous space, it so centered on by preosteoblast (preosteoblast) and Gegenbaur's cell again, occupied the position (ibid) that is similar to arterial wall smooth muscle cell. Bone trabecula (Trabecular bone) Gegenbaur's cell also with marrow endothelial under space have a common boundary (ibid). The people such as Parhami supposition, lipoprotein can pass the bone arterial endothelium, and is deposited on interior subcutaneous space, will experience as oxidation coronarius (ibid) at this. Based on their vitro data, the people such as Parhami prediction is the LDL oxidation in space and the marrow under the bone arterial endothelium, may cause osteoblast differentiation and mineralising to reduce, and this may be the reason (ibid) that causes osteoporosis. Their hypothesis predicts that further the LDL level may be proportionate with osteoporosis, as they the same (Pohle etc. (2001) Circulation with CAC, 104:1927-1932), but the HDL level may be negative correlation (Parhami etc. (1997) Arterioscl Thromb Vasc Biol.17:680-687) with osteoporosis.

[0081] the external osteoblast differentiation of marrow stromal cell M2-10B4 is suppressed by MM-LDL, and is not suppressed (Parhami etc. (1999) J Bone Miner Res. 14:2067-2078) by natural LDL. When the marrow stromal cell of impressibility pulse atherosclerosis C57BL/6 (BL6) mouse that will derive from low fat pellet (chow) diet of feeding is cultivated, Osteoblast Differentiation extremely strong (ibid). By contrast, when to the marrow stromal cell that from higher fatty acid, atherogenic diet mouse, extracts when cultivating, they do not experience Osteoblast Differentiation (ibid). This observed result is very important, because this provides possible explanation (Nuttall and Gimble (2000) Bone, 27:177-184) for marrow stromal cell osteogenic ability in the osteoporosis generating process reduces. The reduction of osteogenic ability increases (ibid) with the Adipogenesis of cancellous bone (osteoporotic bone) in the body.

[0082] we find to add in apoE nude mouse drinking water significantly increases the bone trabecula mineral density in 6 weeks of D-4F, it is believed that other activating agent of the present invention also plays similar action.

[0083] our data show, osteoporosis can be considered as " atherosclerotic of bone ". The result of its seemingly lipid oxide effect. HDL destroys these lipid oxides and promotes osteoblast differentiation. Our data show, give mammal activating agent of the present invention (for example in the drinking water of apoE nude mouse), are only approximately just significantly increasing bone trabecula in several weeks.

[0084] this shows the again calcification that activating agent described herein can be used for one or more symptoms of mitigating osteoporosis disease (for example being used for suppressing decalcification) or is used for inducing cancellous bone. This activating agent is also as preventive medicine, with the generation of prevention mammal (patient that osteoporosis danger is for example arranged) osteoporosis symptom.

[0085] we think that similar mechanism is to cause for example reason of calcific aortic stenosis of CAC. Therefore, in certain embodiments, the present invention includes the symptom of using activating agent described herein to suppress or prevent diseases such as CAC, calcific aortic stenosis, osteoporosis.

E) inflammation indication and autoimmunity indication

[0086] chronic inflammation and/or autoimmune disease also are the features that forms with various active oxygen intermediate, and are suitable for treating with one or more activating agents described herein. Therefore, in the situation that is not subjected to the particular theory constraint, we think that activating agent described herein can be used for one or more symptoms that preventative or therapeutic reduces the outbreak of multiple Other diseases and/or alleviates multiple Other diseases, and described Other diseases includes but not limited to rheumatoid arthritis, lupus erythematosus, PAN, polymyalgia rheumatica, chorionitis, multiple sclerosis etc.

[0087] in certain embodiments, activating agent can be used for alleviating that inflammatory reaction by these diseases causes or relevant one or more symptoms with it.

[0088] same, in certain embodiments, activating agent can be used for alleviating by the reaction of AIDS related inflammation and causes or relevant one or more symptoms with it.

F) infection/wound/transplanting

0089] we find, the result of influenza infection and other infection is paraoxonase and activity of platelet-activating factor acetylhydrolase reduction among the HDL. In the situation that is not subjected to the particular theory constraint, we think, result as these HDL enzymatic activity forfeitures, same result as enzymatic oxidation albumen during acute phase response and HDL association, HDL no longer can prevent the LDL oxidation, and no longer can prevent from inducing through the LDL of endothelial cell the monocyte chemotactic activity of generation.

[0090] we notice, after infecting influenza A virus, inject very some activating agent of the present invention of low dosage (for example 20 micrograms are used for mouse) every day for the curee, the paraoxonase level does not descend, and does not produce foundation level biologically active oxidized phospholipids in addition. This shows and can give (for example oral administration or through injection) patient 4F, D4F (and/or other activating agent of the present invention), described patient comprise such as during the influenza infection or other can produce and knownly during the acute stage inflammatory reaction Other diseases of (such as by due to virus infections, bacterium infection, wound, transplanting, the various autoimmune diseases etc.) suffer from coronary artery disease, so we can prevent the increase of having a heart attack the incidence of disease and producing the cerebral apoplexy related pathologies incidence of disease of this inflammatory conditions by this short.

[0091] in addition, activating agent of the present invention can be used for treatment and infects (for example virus infections, bacterium infection, fungal infection) and/or the inflammatory pathology relevant with infecting (for example meningitis) and/or wound by recovering and/or keeping paraoxonase level and/or monocytic activity.

[0092] in certain embodiments, because anti-inflammatory activity and anti-infection activity combine, therefore activating agent described herein also can be used for treating wound or other wound, alleviates the side effect relevant with following situation: organ or tissue transplants and/or organ or tissue's graft rejection and/or transplanting prosthese and/or transplanted abdominal is atherosis and/or biofilm formation. In addition, we think the effect that L-4F, D-4F and/or other activating agent described herein also can be used for alleviating spinal injury.

G) diabetes and relevant disease

[0093] we find also that various activating agent as herein described has and alleviate and/or the effect of one or more symptoms that prevention is relevant with diabetes. Therefore, in different embodiments, the invention provides the method for the treatment of (therapeutic and/or prophylactic treatment) diabetes and/or related pathologies (such as type i diabetes, type ii diabetes, teenager's disease type diabetes, nephrosis, ephrosis, diabetic neuropathy, diabetic retinopathy etc.).

H) cancer

[0094] NF κ B is the transcription factor that usually is activated when the response proinflammatory cytokine, and it regulates the expression of 200 above genes. Many tumor cell lines show the NF κ B signal transduction of composing type activation. The conclusion of the various researchs of mouse intestinal tumor model and mouse mammary tumor model is the development that tumour has been accelerated in the activation of NF kB pathway, may mainly work in tumorigenic final stage (referring to for example (2004) Cell 118:285; (2004) J.Clin.Invest. 114:569). Suppressing NF κ B signal transduction is obstructed tumor development. Be not subjected in the situation of particular theory constraint, it is generally acknowledged this inhibitions mechanism comprise increase apoptosis of tumor cells, reduce around the growth of tumour cell factor that provides of stroma cell expression and/or to eliminate tumor-infiltrated/transfer be that very important tumour cell dedifferentes program.

[0095] be not subjected in the situation of particular theory constraint, we think and give expression and/or secretion and/or the activity that one or more activating agents described herein will suppress NF κ B. Therefore, in certain embodiments, the present invention provides the method for the treatment of take NF κ B rising as the pathology of feature by giving one or more activating agents described herein. Therefore, in different embodiments, the present invention includes by giving one or more activating agents described herein, optional and suitable cancer therapy coupling is to suppress the cancer relevant with the NF kB activation.

I) biochemical activity

[0096] activating agent described herein has shown many specific biologically actives. For example, their increase Heme oxygenase 1, increase SOD-3, reduce or prevent myeloperoxidase and apoA-I associate, reduce or prevent tyrosine among the apoA-I nitrosylation, make HDL become anti-inflammatory or anti-inflammatory is bigger, increase before the effect of the formation of β HDL and circulation, the reverse cholesterol transport of the promotion reverse cholesterol transport of macrophage (specifically, from), enhancing inhibin. Therefore, any that can give that mammal activating agent described herein promotes these activity, treatment for example its order of severity and/or outbreak possibility by the disease/pathology of one or more reductions in these activity.

J) alleviate the atherosclerotic symptom relevant with acute inflammatory reaction

[0097] activating agent of the present invention also can be used for many aspects.For example, we find that cardiovascular complication (for example atherosclerosis, apoplexy etc.) often takes place with the acute stage inflammatory reaction or in acute stage inflammatory reaction (for example with relevant acute stage inflammatory reactions such as recurrent inflammatory diseases, viral infection (for example influenza), bacterial infection, fungal infection, organ transplantation, wound or other wounds) outbreak back.

[0098] therefore, in certain embodiments, the present invention includes and give the curee one or more activating agents described herein, this patient has the acute inflammatory reaction risk or suffers from acute inflammatory reaction and/or atherosclerosis is arranged and/or the risk of related pathologies (for example apoplexy) symptom or suffer from atherosclerosis and/or the symptom of related pathologies.

[0099] therefore, for example in influenza season, the coronary artery disease risk can prophylactically be arranged or suffer from one or more activating agents of the present invention of individuality of coronary artery disease.For the people (or animal) of easy trouble recurrent inflammatory diseases (for example rheumatoid arthritis, various autoimmune diseases etc.), can treat to alleviate or prevention of arterial is atherosis or the development of apoplexy with one or more activating agents described herein.For the people (or animal) of easy trouble wound (for example acute injury, tissue transplantation etc.), can treat to slow down the development of atherosclerosis or apoplexy with polypeptide of the present invention.

[0100] in some cases, this method is that the generation or the risk of diagnosing acute inflammatory reaction is necessary.Acute inflammatory reaction is usually directed to the change of liver intracellular metabolite and Gene regulation.This is one and relates in the body except that the unify dynamic steady state process of all main systems the central nervous system of immune system, cardiovascular system.Acute phase response generally only continues a few days, yet, under the situation of chronic inflammatory disease or recurrent inflammation, the unusual prolongation in some aspect of acute phase response may be one of the reason of the vital tissue damage of accompanying diseases, also may cause other complication, for example cardiovascular disease or proteins deposited disease amyloidosis for example.

[0101] acute phase response importance is liver the biosynthesis feature sharply changes.Under normal circumstances, liver is with the plasma proteins in the Css composite character scope.Many in these protein have critical function, and the acute phase response phase behind inflammatory stimulus, and the higher blood plasma level of these acute phase reactants (APR) or acute phase protein (APP) is essential.Although most of APR are synthetic by hepatocyte, some APR are produced by other cell type, comprise mononuclear cell, endotheliocyte, fibroblast and adipose cell.Most of APR through inducing generation are between 50% and several times of normal level.By contrast, the then comparable normal level of main APR increases by 1000 times.This group comprises congener, the serum amyloid sample ingredient (SAP) in serum amyloid A component (SAA), human C-reactive albumen (CRP) or its mice.During acute phase response, the plasma concentration of so-called negative APR reduces increases the ability of the synthetic inductive APR of liver.

[0102] in certain embodiments, therefore estimate acute phase response or risk by measuring one or more APP.The mensuration of these labellings is well-known to those skilled in the art, has commercial enterprise that this mensuration (for example by Cardiotech Services, Louisville, KY measures AGP) is provided.

K) other indication

[0103] in different embodiments, it is generally acknowledged that activating agent described herein can be used for that treatment (for example alleviate and/or prevent) corneal ulcer, endothelium come off, Crohn disease, Acute and chronic dermatitis (including but not limited to eczema and/or psoriasis), degeneration of macula, neuropathy, scleroderma and ulcerative colitis.

[0104] table 1 is that activating agent is demonstrated effectively and/or it is believed that it is effective indication/disease catalog.

[0105] table 1. pair activating agent (for example D-4F) demonstrates effectively and/or it is believed that it is effective disease catalog.

Atherosclerosis/symptom/speckle forms pathological changes formation myocardial infarction apoplexy as a result
	Congestive heart failure
Vascular function: the aging-related Alzheimer dependency of arteriole function arteriole disease chronic nephropathy dependency hypertension dependency multi-infarct dementia dependency subarachnoid hemorrhage dependency peripheral blood vessel
	Pneumonopathy: chronic obstructive disease of lung (COPD) emphysema asthma idiopathic pulmonary fibrosis pulmonary fibrosis adult respiratory distress syndrome
Osteoporosis
	Paget
Coronary artery calcification
	Autoimmune disease: rheumatoid arthritis

Polyarteritis nodosa polymyalgia rheumatica lupus erythematosus multiple sclerosis Wegner granulomatosis central nervous system's vasculitis (CNSV) xerodermosteosis scleroderma polymyositis
	The AIDS inflammatory reaction
Infect: bacterial infection fungal infection viral infection parasitic infection influenza avian influenza toxicity pneumonia endotoxin shock syndrome sepsis sepsis syndrome (clinical symptoms that the patient occurs is a sepsis, but does not isolate organism from blood)
	Wound/wound: atherosclerosis transplant rejection corneal ulcer is transplanted in organ transplantation

Chronic/disunion wound ulcer colitis reperfusion injury (preventing and/or treating) ischemia reperfusion damage (preventing and/or treating) spinal cord injury (alleviating effect)
	Cancer bone myeloma/multiple myeloma ovarian cancer breast carcinoma colon cancer osteocarcinoma
Osteoarthritis
	Inflammatory bowel
Allergic rhinitis
	Cachexia
Diabetes
	Alzheimer
Implanting prosthetic
	Biomembrane forms
Crohn disease
	Acute dermatitis and chronic dermatitis eczema psoriasis contact dermatitis scleroderma
Diabetes and relevant disease type i diabetes type ii diabetes

Teenager disease type diabetes mellitus prevention diabetes outbreak diabetic nephropathy diabetic neuropathy diabetic retinopathy
	Erection disturbance
Degeneration of macula
	Multiple sclerosis
Nephropathy
	Neuropathy
Parkinson disease
	Peripheral blood vessel
Meningitis
	The specific biological activity: increasing Heme oxygenase 1 increases SOD-3 and prevents that endothelium from coming off and prevent that myeloperoxidase (MPO) and ApoA-I from associating and prevent that the formation of β HDL promotes reverse cholesterol transport to promote the effect of the reverse cholesterol transport enhancing inhibin of macrophage before the nitrosylation of tyrosine increases HDL inflammation and improving vascular reactivity among the ApoA-I

[0106] is noted that the listed disease of table 1 is exemplary and not restrictive.

L) administration

[0107] activating agent can there be the mammal (for example people) that needs usually.Described mammal generally includes to be suffered from one or more pathology described herein or the mammal (for example people) that suffers from one or more risk of pathologies described herein is arranged.

[0108] can give activating agent as herein described according to any of many standard methods, these methods include but not limited to injection, suppository, nasal mist, sustained-release implant, transdermal patch etc.In an especially preferred embodiment, this peptide oral administration (for example syrup, capsule or tablet) gives.

[0109] this method comprises and gives single activating agent of the present invention or give two or more different activating agents.Activating agent can be used as monomeric form (for example separate dosage forms or mixing dosage form) or provides as dimeric forms, oligomer form or polymer form.In certain embodiments, the polymer form can comprise associating monomer (for example monomer of ionic bond or hydrophobic bond connection), and some other polymer form then comprises covalently bound monomer (directly connect or connect by joint).

[0110] though the present invention has introduced the relevant people's of being used for purposes, it also is applicable to animal, for example veterinary purpose.For example, some preferred biology includes but not limited to animals such as people, non-human primates, dog, horse, cat, pig, ungulate, largomorphs.

[0111] method of the present invention is not limited to show the people or the non-human animal of one or more symptoms of pathology described herein, also can be used for the prevention aspect.Therefore, activating agent of the present invention can give the outbreak/development of organism one or more symptoms (for example atherosclerosis, apoplexy etc.) to prevent pathology described herein.At this on the one hand, particularly preferred curee is the curee who shows one or more risk factor of described pathology.For example, in atherosclerosis, risk factor comprise family history, hypertension, obesity, high alcohol consumption, smoking, high blood cholesterol, high blood triglyceride, high blood LDL, VLDL, IDL or low HDL, diabetes or diabetes family history, hyperlipidemia matter, heart attack, angina pectoris or apoplexy, or the like.

II. activating agent

[0112] various activating agents are applicable to one or more indications discussed above of treatment.These activating agents include but not limited to category-A amphipathic helix peptide, have the category-A amphipathic helix peptide mimics of the apoA-I of aromatic moieties or aliphatic residue at non-polar plane, comprise pentapeptide, tetrapeptide, tripeptides, dipeptides and paired amino acid whose little peptide, Apo-J (G ^*Peptide) and peptide mimics (for example, as described below).

A) category-A amphipathic helix peptide

[0113] in certain embodiments, the activator that is used for the inventive method comprises category-A amphipathic helix peptide, for example referring to United States Patent (USP) 6,664, and 230 and PCT publication No. WO02/15923 and WO 2004/034977.Have now found that, comprise the peptide (" category-A peptide ") of category-A amphipathic helix, except can alleviating atherosclerotic one or more symptoms, also can be used for treating one or more other indications as herein described.

[0114] feature of category-A peptide is the alpha-helix that forms polarization residue and non-polar residue separation, thereby form polar surface and non-polar plane, wherein positively charged residue is present in the polar-nonpolar interface, electronegative residue then is present in the center of polar surface (referring to for example Anantharamaiah (1986) Meth.Enzymol, 128:626-668).Be noted that the 4th exon of apoA-I, when being folded into 3.667 residues/corner (residue/turn), produce category-A amphipathic helix structure.

[0115] presses a kind of category-A peptide to called after 18A described herein (referring to for example Anantharamaiah (1986) Meth.Enzymol, 128:626-668) modify, produce Orally-administrable, suppressing or prevent the very effective peptide of one or more symptoms of atherosclerosis and/or other indication described herein.Under the situation that is not subjected to the particular theory constraint, we think that peptide of the present invention can work in vivo by selecting to reduce the seeding molecule of LDL oxidation.

[0116] we determine to increase the quantity of 18A hydrophobic surface Phe residue, can increase the lipid affinity in theory, as people such as Palgunachari ((1996) Arteriosclerrosis, Thrombosis ， ﹠amp; What Vascular Biol.16:328-338) computing method of being introduced was measured is the same.In theory, the residue of 18A non-polar plane can be produced six peptides by the replacement of Phe systematicness.Peptide with extra 2,3 and 4 Phe, lipid affinity (λ) theoretical value is respectively 13,14 and 15 units.Yet, if extra Phe is increased to 5 from 4, λ value 4 units (to 19 λ units) that jump.Increase to 6 or 7 Phe, can produce increases (respectively to 20 and 21 λ units) not too significantly.

[0117] can prepare the multiple category-A peptide of peptides such as comprising called after 4F, D4F, 5F and D5F.Various category-A peptides all suppress the pathological development of impressibility pulse atherosclerosis mice.In addition, described peptide is when alleviating one or more symptoms of different pathological described herein, and effect is different but very remarkable.Table 2 has been enumerated many such peptides.

[0118] table 2. is used for exemplary category-A amphipathic helix peptide of the present invention.

The peptide title	Aminoacid sequence	SEQ ID NO.
			18A 2F 3F 3F14 4F 5F 6F 7F	D-W-L-K-A-F-Y-D-K-V-A-E-K-L-K-E-A-F Ac-D-W-L-K-A-F-Y-D-K-V-A-E-K-L-K-E-A-F-NH 2 Ac-D-W-F-K-A-F-Y-D-K-V-A-E-K-L-K-E-A-F-NH 2 Ac-D-W-L-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-NH 2 Ac-D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-NH 2 Ac-D-W-L-K-A-F-Y-D-K-V-F-E-K-F-K-E-F-F-NH 2 Ac-D-W-L-K-A-F-Y-D-K-F-F-E-K-F-K-E-F-F-NH 2 Ac-D-W-F-K-A-F-Y-D-K-F-F-E-K-F-K-E-F-F-NH 2 Ac-D-W-L-K-A-F-Y-D-K-V-A-E-K-L-K-E-F-F-NH 2 Ac-D-W-L-K-A-F-Y-D-K-V-F-E-K-F-K-E-A-F-NH 2 Ac-D-W-L-K-A-F-Y-D-K-V-F-E-K-L-K-E-F-F-NH 2 Ac-D-W-L-K-A-F-Y-D-K-V-A-E-K-F-K-E-F-F-NH 2 Ac-D-W-L-K-A-F-Y-D-K-V-F-E-K-F-K-E-F-F-NH 2 Ac-E-W-L-K-L-F-Y-E-K-V-L-E-K-F-K-E-A-F-NH 2 Ac-E-W-L-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-NH 2 Ac-E-W-L-K-A-F-Y-D-K-V-A-E-K-L-K-E-F-F-NH 2 Ac-E-W-L-K-A-F-Y-D-K-V-F-E-K-F-K-E-A-F-NH 2 Ac-E-W-L-K-A-F-Y-D-K-V-F-E-K-L-K-E-F-F-NH 2 Ac-E-W-L-K-A-F-Y-D-K-V-A-E-K-F-K-E-F-F-NH 2 Ac-E-W-L-K-A-F-Y-D-K-V-F-E-K-F-K-E-F-F-NH 2 Ac-A-F-Y-D-K-V-A-E-K-L-K-E-A-F-NH 2 Ac-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-NH 2 Ac-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-NH 2 Ac-A-F-Y-D-K-F-F-E-K-F-K-E-F-F-NH 2 Ac-A-F-Y-D-K-F-F-E-K-F-K-E-F-F-NH 2 Ac-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-NH 2 Ac-A-F-Y-D-K-V-A-E-K-L-K-E-F-F-NH 2 Ac-A-F-Y-D-K-V-F-E-K-F-K-E-A-F-NH 2 Ac-A-F-Y-D-K-V-F-E-K-L-K-E-F-F-NH 2 Ac-A-F-Y-D-K-V-A-E-K-F-K-E-F-F-NH 2 Ac-K-A-F-Y-D-K-V-F-E-K-F-K-E-F-NH 2 Ac-L-F-Y-E-K-V-L-E-K-F-K-E-A-F-NH 2 Ac-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-NH 2 Ac-A-F-Y-D-K-V-A-E-K-L-K-E-F-F-NH 2 Ac-A-F-Y-D-K-V-F-E-K-F-K-E-A-F-NH 2 Ac-A-F-Y-D-K-V-F-E-K-L-K-E-F-F-NH 2 Ac-A-F-Y-D-K-V-A-E-K-F-K-E-F-F-NH 2 Ac-A-F-Y-D-K-V-F-E-K-F-K-E-F-F-NH 2	1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38

Ac-D-W-L-K-A-L-Y-D-K-V-A-E-K-L-K-E-A-L-NH 2 Ac-D-W-F-K-A-F-Y-E-K-V-A-E-K-L-K-E-F-F-NH 2 Ac-D-W-F-K-A-F-Y-E-K-F-F-E-K-F-K-E-F-F-NH 2 Ac-E-W-L-K-A-L-Y-E-K-V-A-E-K-L-K-E-A-L-NH 2 Ac-E-W-L-K-A-F-Y-E-K-V-A-E-K-L-K-E-A-F-NH 2 Ac-E-W-F-K-A-F-Y-E-K-V-A-E-K-L-K-E-F-F-NH 2 Ac-E-W-L-K-A-F-Y-E-K-V-F-E-K-F-K-E-F-F-NH 2 Ac-E-W-L-K-A-F-Y-E-K-F-F-E-K-F-K-E-F-F-NH 2 Ac-E-W-F-K-A-F-Y-E-K-F-F-E-K-F-K-E-F-F-NH 2 Ac-D-F-L-K-A-W-Y-D-K-V-A-E-K-L-K-E-A-W-NH 2 Ac-E-F-L-K-A-W-Y-E-K-V-A-E-K-L-K-E-A-W-NH 2 Ac-D-F-W-K-A-W-Y-D-K-V-A-E-K-L-K-E-W-W-NH 2 Ac-E-F-W-K-A-W-Y-E-K-V-A-E-K-L-K-E-W-W-NH 2 Ac-D-K-L-K-A-F-Y-D-K-V-F-E-W-A-K-E-A-F-NH 2 Ac-D-K-W-K-A-V-Y-D-K-F-A-E-A-F-K-E-F-L-NH 2 Ac-E-K-L-K-A-F-Y-E-K-V-F-E-W-A-K-E-A-F-NH 2 Ac-E-K-W-K-A-V-Y-E-K-F-A-E-A-F-K-E-F-L-NH 2 Ac-D-W-L-K-A-F-V-D-K-F-A-E-K-F-K-E-A-Y-NH 2 Ac-E-K-W-K-A-V-Y-E-K-F-A-E-A-F-K-E-F-L-NH 2 Ac-D-W-L-K-A-F-V-Y-D-K-V-F-K-L-K-E-F-F-NH 2 Ac-E-W-L-K-A-F-V-Y-E-K-V-F-K-L-K-E-F-F-NH 2 Ac-D-W-L-R-A-F-Y-D-K-V-A-E-K-L-K-E-A-F-NH 2 Ac-E-W-L-R-A-F-Y-E-K-V-A-E-K-L-K-E-A-F-NH 2 Ac-D-W-L-K-A-F-Y-D-R-V-A-E-K-L-K-E-A-F-NH 2 Ac-E-W-L-K-A-F-Y-E-R-V-A-E-K-L-K-E-A-F-NH 2 Ac-D-W-L-K-A-F-Y-D-K-V-A-E-R-L-K-E-A-F-NH 2 Ac-E-W-L-K-A-F-Y-E-K-V-A-E-R-L-K-E-A-F-NH 2 Ac-D-W-L-K-A-F-Y-D-K-V-A-E-K-L-R-E-A-F-NH 2 Ac-E-W-L-K-A-F-Y-E-K-V-A-E-K-L-R-E-A-F-NH 2 Ac-D-W-L-K-A-F-Y-D-R-V-A-E-R-L-K-E-A-F-NH 2 Ac-E-W-L-K-A-F-Y-E-R-V-A-E-R-L-K-E-A-F-NH 2 Ac-D-W-L-R-A-F-Y-D-K-V-A-E-K-L-R-E-A-F-NH 2 Ac-E-W-L-R-A-F-Y-E-K-V-A-E-K-L-R-E-A-F-NH 2 Ac-D-W-L-R-A-F-Y-D-R-V-A-E-K-L-K-E-A-F-NH 2 Ac-E-W-L-R-A-F-Y-E-R-V-A-E-K-L-K-E-A-F-NH 2 Ac-D-W-L-K-A-F-Y-D-K-V-A-E-R-L-R-E-A-F-NH 2 Ac-E-W-L-K-A-F-Y-E-K-V-A-E-R-L-R-E-A-F-NH 2

39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75

Ac-D-W-L-R-A-F-Y-D-K-V-A-E-R-L-K-E-A-F-NH 2 Ac-E-W-L-R-A-F-Y-E-K-V-A-E-R-L-K-E-A-F-NH 2 D-W-L-K-A-F-Y-D-K-V-A-E-K-L-K-E-A-F -P-D-W- L-K-A-F-Y-D-K-V-A-E-K-L-K-E-A-F D-W-L-K-A-F-Y-D-K-V-A-E-K-L-K-E-F-F -P-D-W- L-K-A-F-Y-D-K-V-A-E-K-L-K-E-F-F D-W-F-K-A-F-Y-D-K-V-A-E-K-L-K-E-A-F -P-D-W- F-K-A-F-Y-D-K-V-A-E-K-L-K-E-A-F D-K-L-K-A-F-Y-D-K-V-F-E-W-A-K-E-A-F -P-D-K- L-K-A-F-Y-D-K-V-F-E-W-L-K-E-A-F D-K-W-K-A-V-Y-D-K-F-A-E-A-F-K-E-F-L -P-D-K- W-K-A-V-Y-D-K-F-A-E-A-F-K-E-F-L D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F -P-D-W- F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F D-W-L-K-A-F-V-Y-D-K-V-F-K-L-K-E-F-F -P-D-W- L-K-A-F-V-Y-D-K-V-F-K-L-K-E-F-F D-W-L-K-A-F-Y-D-K-F-A-E-K-F-K-E-F-F -P-D-W- L-K-A-F-Y-D-K-F-A-E-K-F-K-E-F-F Ac-E-W-F-K-A-F-Y-E-K-V-A-E-K-F-K-E-A-F-NH 2 Ac-D-W-F-K-A-F-Y-D-K-V-A-E-K-F-NH 2 Ac-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-NH 2 Ac-F-K-A-F-Y-E-K-V-A-E-K-F-K-E-NH 2 NMA-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-NH 2 NMA-F-K-A-F-Y-E-K-V-A-E-K-F-K-E-NH 2 NMA-D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-NH 2 NMA-E-W-F-K-A-F-Y-E-K-V-A-E-K-F-K-E-A-F-NH 2 NMA-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-NH 2 NMA-D-W-F-K-A-F-Y-D-K-V-A-E-K-F-NH 2 Ac-D-W-L-K-A-F-Y-D-K-V-F-E-K-F-K-E-F-F-NH 2 NMA-D-W-L-K-A-F-Y-D-K-V-F-E-K-F-K-E-F-F-NH 2 Ac-E-W-L-K-A-F-Y-E-K-V-F-E-K-F-K-E-F-F-NH 2 NMA-E-W-L-K-A-F-Y-E-K-V-F-E-K-F-K-E-F-F-NH 2 Ac-A-F-Y-D-K-V-F-E-K-F-K-E-F-F-NH 2 NMA-A-F-Y-D-K-V-F-E-K-F-K-E-F-F-NH 2 Ac-A-F-Y-E-K-V-F-E-K-F-K-E-F-F-NH 2 NMA-A-F-Y-E-K-V-F-E-K-F-K-E-F-F-NH 2 Ac-D-W-L-K-A-F-Y-D-K-V-F-E-K-F-NH 2 NMA-D-W-L-K-A-F-Y-D-K-V-F-E-K-F-NH 2 Ac-E-W-L-K-A-F-Y-E-K-V-F-E-K-F-NH 2

76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101

NMA-E-W-L-K-A-F-Y-E-K-V-F-E-K-F-NH 2 Ac-L-K-A-F-Y-D-K-V-F-E-K-F-K-E-NH 2 NMA-L-K-A-F-Y-D-K-V-F-E-K-F-K-E-NH 2 Ac-L-K-A-F-Y-E-K-V-F-E-K-F-K-E-NH 2 NMA-L-K-A-F-Y-E-K-V-F-E-K-F-K-E-NH 2

102 103

¹Joint underlines.

NMA is a N-methyl o-amino benzoyl acyl group.

[0119] in certain preferred aspects, this peptide comprises 4F (variant of (being SEQ IDNO:5 in the table 2) also claims L-4F, and wherein all residues all are L type aminoacid), perhaps comprises D-4F, and wherein one or more residues are D type aminoacid).In arbitrary peptide described herein, C end and/or N end and/or inner residue can seal with one or more blocking groupses as herein described.

[0120] though having enumerated with acetyl group or N-methyl o-amino benzoyl acyl group (N-methylanthranilyl), table 2 protects the N end; with the various peptides of amide groups protection C end, but any of these protecting group can be sloughed and/or with another protecting group replacement described herein.In an especially preferred embodiment, this peptide comprises one or more D type aminoacid as herein described.In certain embodiments, each aminoacid of peptide (for example each enantiomer aminoacid) all is D type aminoacid in the table 2.

It is also noted that [0121] table 2 is not all to be included.Use instruction provided herein, can produce other proper A class amphipathic helix peptide (for example can replace or half conservative (for example D replaces with E), extension, the disappearance etc. of replacing) routinely by conservative.For example, embodiment is used the truncate of any one or more peptide (for example SEQ IDNo:2-20 and 39 peptides of being identified in the table 2) shown in this paper.For example, SEQ ID NO:21 represents to comprise 14 amino acid whose peptides from the C end of 18A, wherein comprises one or more D aminoacid, and SEQ ID NO:22-38 then represents other truncated peptide.

[0122] long peptide also suits.Long peptide can intactly form the category-A amphipathic helix, and perhaps the category-A amphipathic helix can form one or more domains of peptide.In addition, the present invention includes the peptide (for example concatemer) of polymer form.For example, peptide cited herein can be coupled at together (interleave the direct coupling of aminoacid or pass through joint (for example carbon atom joint or one or more aminoacid) with one or more).Exemplary polymer peptide comprises the peptide of 18A-Pro-18A and SEQ ID No:78-85, comprises one or more D aminoacid in certain embodiments, and more preferably each aminoacid all is that D aminoacid as herein described and/or one or both ends are protected.

Should also be understood that except that the peptide sequence that this paper clearly enumerates that [0123] the present invention also comprises each reverse type (retro form) and reverse contrary type form (retro-inverso form) of these peptides.In reverse type, the direction of sequence is opposite.In contrary type form, the amino acid whose chirality of composition is opposite (that is to say that L type aminoacid becomes D type aminoacid, D type aminoacid becomes L type aminoacid).In reverse contrary type form, amino acid whose order and chirality all are opposite.For example, 4F peptide (DWFKAFYDKVAEKFKEAF, SEQID NO:5), wherein the N end is aspartic acid (D), and the C end is phenylalanine (F), and its reverse type has identical sequence, but the N end is phenylalanine, and the C end is aspartic acid (being FAEKFKEAVKDYFAKFWD, SEQ ID NO:104).When the 4F peptide comprises all L aminoacid, the sequence (SEQ ID NO:104) as implied above of then reverse contrary type form, and comprise all D type aminoacid.Shown in the spiral colyliform figure of Figure 15,4F and reverse contrary type peptide (Rev-4F) be mirror image each other, have the identical polar surface and the separation of non-polar plane, positively charged residue is present in the interface of polar-nonpolar, and electronegative residue then is present in the center of polar surface.With regard to the separation of polar surface and non-polar plane, positively charged residue is present in the interface of polar-nonpolar, and electronegative residue is present in the center of polar surface, and the identical polymeric mirror image of aminoacid is identical.Therefore, 4F and Rev-4F are enantiomer each other.Argumentation for reverse peptide and reverse contrary type peptide can be referring to for example Chorev and Goodman, (1995) TibTech, 13:439-445.

[0124] when mentioning that sequence does not offer some clarification on direction again, sequence can be considered expression N and holds to the aminoacid sequence of C extreme direction, reverse type (being that C holds to the aminoacid sequence of N extreme direction), L aminoacid is replaced by D aminoacid in the reverse type, perhaps D aminoacid is replaced by L aminoacid, then is the also opposite reverse contrary type form of reversed in order and amino acid chiral.

C) to have aromatics at non-polar plane residual for the category-A amphipathic helix peptide mimics of apoA-I Base or aliphatic residue

[0125] in certain embodiments, the present invention also provides the category-A amphipathic helix peptide of modification.Some preferred peptide comprises one or more aromatic moieties, for example 3F at the non-polar plane center ^{C π}(as being present among the 4F), perhaps have one or more aliphatic residues, for example 3F at the non-polar plane center ^{I π}, referring to for example table 3.Be not subjected under the situation of particular theory constraint, we think peptide 3F ^{C π}The center aromatic moieties of non-polar plane, because the existence of non-polar plane center pi-electron, allow near the hydrophobic lipid alkyl chain of hydrone across and into peptide-lipid complex, and then can make the reactive oxygen intermediate that is shielded by cell surface enter (for example lipid hydroperoxide).Similarly, we also think to have the peptide of aliphatic residue at the non-polar plane center, for example 3F ^{I π}To play similar but and 3F ^{C π}Same effective function.

[0126] preferred peptide can make short scorching HDL be transformed into antiinflammatory HDL or make antiinflammatory HDL antiinflammatory and/or reduce the inductive monocyte chemotactic activity of LDL that arterial wall cell produced to the effect that is equal to or greater than other peptide shown in D4F or the table 2 more.

[0127] example of some preferred peptide of table 3..

Title	Sequence	SEQ ID NO
			(3F Cπ)(3F Iπ)	Ac-DKWKAVYDKFAEAFKEFL-NH 2 Ac-DKLKAFYDKVFEWAKEAF-NH 2	105 106

C) other category-A amphipathic helix peptide and some Y class amphipathic helix peptides

[0128] in certain embodiments, the present invention also comprises having the category-A amphipathic helix peptide of forming with above-mentioned one or more category-A amphipathic helix peptide same amino acid.For example, in certain embodiments, the present invention includes the peptide of forming with the 4F same amino acid.Therefore, in certain embodiments, the present invention includes activating agent, this activating agent comprises the peptide of being made up of 18 aminoacid, and wherein 18 aminoacid are made up of 3 alanine (A), 2 aspartic acids (D), 2 glutamic acid (E), 4 phenylalanine (F), 4 lysines (K), 1 valine (V), 1 tryptophan (W) and 1 tyrosine (Y); And peptide forms the category-A amphipathic helix; Protection phospholipid makes its not oxidized dose of oxidation.In different embodiments, this peptide comprises at least one " D " amino acid residue; In certain embodiments, this peptide comprises all D type amino acid residues.Table 4 has exemplified multiple such peptide.In reverse (reverse) of these peptides, contrary type, reverse contrary type and cyclic sequence change (circularly permuted) form are also included within.

[0129] table 4. has the exemplary category-A amphipathic helix peptide of 18 amino acid lengths of following aminoacid composition: 3 alanine (A), 2 aspartic acids (D), 2 glutamic acid (E), 4 phenylalanine (F), 4 lysines (K), 1 valine (V), 1 tryptophan (W) and 1 tyrosine (Y).

Title	Sequence	SEQ ID NO
			[conversion D-E]-4F analog		107
[conversion D-E]-1-4F	Ac- EWFKAFY EKVA DKFK DAF-NH2	108
			[conversion D-E]-2-4F	Ac- EWFKAFYDKVADKFK EAF-NH2	109

[conversion D-E]-3-4F	Ac-DWFKAFY EKVA DKFKEAF-NH2	110
			[conversion D-E]-4-4F	Ac-DWFKAFY EKVAEKFK DAF-NH2	111
[W-2, F-3 is out of position]		112
			4F-2	Ac-D FWKAFYDKVAEKFKEAF-NH 2	113
[conversion D-E]-1-4F-2	Ac- EFWKAY EKVA DKFK DAF-NH2	114
			[conversion D-E]-2-4F-2	Ac- EFWKAFYDKVADKFK EAF-NH2	115
[conversion D-E]-3-4F-2	Ac-DFWKAFY EKVA DKFKEAF-NH2	116
			[conversion D-E]-4-4F-2	Ac-DFWKAFY EKVAEKFK DAF-NH2	117
[F-6 and the conversion of Y-7 position]		118
			4F-3	Ac-DWFKA YFDKVAEKFKEAF-NH 2	119
[conversion D-E]-1-4F-5	Ac- EWFKAYE EKVA DKFK DAF-NH2	120
			[conversion D-E]-2-4F-5	Ac- EWFKAYFDKVADKFK EAF-NH2	121
[conversion D-E]-3-4F-5	Ac-DWFKAYF EKVA DKFKEAF-NH2	122
			[conversion D-E]-4-4F-5	Ac-DWFKAYF EKVAEKFK DAF-NH2	123
[Y-7 and the conversion of 10V position]		124
			4F-4	Ac-DWFKAF VDK YAEKFKEAF-NH 2	125
[conversion D-E]-1-4F-4	Ac- EWFKAFV EKYA DKFK DAF-NH2	126
			[conversion D-E]-2-4F-4	Ac- EWFKAFVDKYADKFK EAF-NH2	127
[conversion D-E]-3-4F-4	Ac-DWFKAFV EKYA DKFKEAF-NH2	128
			[conversion D-E]-4-4F	Ac-DWFKAFV EKYAEKFK DAF-NH2	129
[V-10 and A-11 conversion]		130
			4-F-5	Ac-DWFKAFYDK AVEKFKEAF-NH 2	131
[conversion D-E]-1-4F-5	Ac- EWFKAFY EKAV DKFK DAF-NH2	132
			[conversion D-E]-2-4F-5	Ac- EWFKAFYDKAVDKFK EAF-NH2	133
[conversion D-E]-3-4F-5	Ac-DWFKAFY EKAV DKFKEAF-NH2	134
			[conversion D-E]-4-4F-5	Ac-DWFKAFY EKAVEKFK DAF-NH2	135
[A-11 and F-14 conversion]		136
			4F-6	Ac-DWFKAFYDKV FeK AKEAF-NH 2	137
[conversion D-E]-1-4F-6	Ac- EWFKAFY EKVF DKAK DAF-NH2	138
			[conversion D-E]-2-4F-6	Ac- EWFKAFYDKVFDKAK EAF-NH2	139
[conversion D-E]-3-4F-6	Ac-DWFKAFY EKVF DKAKEAF-NH2	140
			[conversion D-E]-4-4F-6	Ac-DWFKAFY EKVFEKAK DAF-NH2	141
[F-14 and A-17 conversion]		142
			4F-7	Ac-DWFKAFYDKVAEK AKE FF-NH 2	143
[conversion D-E]-1-4F-7	Ac- EWFKAFY EKVA DKAK DFF-NH2	144
			[conversion D-E]-2-4F-7	Ac- EWFKAFYDKVADKAK EFF-NH2	145
[conversion D-E]-3-4F-7	Ac-DWFKAFY EKVA DKAKEFF-NH2	146
			[conversion D-E]-4-4F-7	Ac-DWFKAFY EKVAEKAK DFF-NH2	147
[A-17 and F-18 conversion]		148
			4F-8	Ac-DWFKAFYDKVAEKFKE FA-NH 2	149
[conversion D-E]-1-4F-8	Ac- EWFKAFY EKVA DKFK DFA-NH2	150
			[conversion D-E]-2-4F-8	Ac- EWFKAFYDKVADKF EFA-NH2	151
[conversion D-E]-3-4F-8	Ac-DWFKAFY EKVA DKFKEFA-NH2	152
			[conversion D-E]-4-4F-8	Ac-DWFKAFY EKVAEKFK DFA-NH2	153
[W-2 and A-17 conversion]		154
			4F-9	Ac-D AFKAFYDKVAEKFKE WF-NH 2	155
[conversion D-E]-1-4F-9	Ac- EAFKAFY EKVA DKFK DWF-NH2	156
			[conversion D-E]-2-4F-9	Ac- EAFKAFYDKVADKFK EWF-NH2	157
[conversion D-E]-3-4F-9	Ac-DAFKAFY EKVA DKFKEWF-NH2	158
			[conversion D-E]-4-4F-9	Ac-DAFKAFY EKVAEKFK DWF-NH2	159
[W-2 and A-11 conversion]		160
			4F-10	Ac-D AFKAFYDKV WEKFKEAF-NH 2	161
[conversion D-E]-1-4F-10	Ac- EAFKAFY EKVW DKFK DAF-NH2	162

[conversion D-E]-2-4F-10	Ac- EAFKAFYDKVWDFKK EAF-NH2	163
			[conversion D-E]-3-4F-10	Ac-DAFKAFY EKVW DKFKEAF-NH2	164
[conversion D-E]-4-4F-10	Ac-DAFKAFY EKVWEKFK DAF-NH2	165
			[W-2 and Y-7 conversion]		166
4F-11	Ac-D YFKAF WDKVAEKFKEAF-NH 2	167
			[conversion D-E]-1-4F-11	Ac- EYFKAFW EKVA DKFK DAF-NH2	168
[conversion D-E]-2-4F-11	Ac- EYFKAFWDKVADKFK EAF-NH2	169
			[conversion D-E]-3-4F-11	Ac-DYFKAFW EKVA DKFKEAF-NH2	170
[conversion D-E]-4-4F-11	Ac-DYFKAFW EKVAEKFK DAF-NH2	171
			[F-3 and A-17 conversion]		172
4F-12	Ac-DW AKAFYDKVAEKFKE FF-NH 2	173
			[conversion D-E]-1-4F-12	Ac- EWAKAFY EKVA DKFK DFF-NH2	174
[conversion D-E]-2-4F-12	Ac- EWAKAFYDKVADKFK EFF-NH2	175
			[conversion D-E]-3-4F-12	Ac-DWAKAFY EKVA DKFKEFF-NH2	176
[conversion D-E]-4-4F-12	Ac-DWAKAFY EKVAEKFK DFF-NH2	177
			[F-6 and A-17 conversion]		178
4F-13	Ac-DWFKA AYDKVAEKFKE FF-NH 2	179
			[conversion D-E]-1-4F-13	Ac- EWFKAAY EKVA DKFK DFF-NH2	180
[conversion D-E]-2-4F-13	Ac- EWFKAAYDKVADKFK EFF-NH2	181
			[conversion D-E]-3-4F-13	Ac-DWFKAAY EKVA DKFKEFF-NH2	182
[conversion D-E]-4-4F-13	Ac-DWFKAAY EKVAEKFK DFF-NH2	183
			[Y-7 and A-17 conversion]		184
4F-14	Ac-DWFKAF ADKVAEKFKE YF-NH 2	185
			[conversion D-E]-1-4F-14	Ac- EWFKAFA EKVADKFK DYF-NH2	186
[conversion D-E]-2-4F-14	Ac- EWFKAFADKVADKFK EYF-NH2	187
			[conversion D-E]-3-4F-14	Ac-DWFKAFA EKVA DKFKEYF-NH2	188
[conversion D-E]-4-4F	Ac-DWFKAFA EKVAEKFK DYF-NH2	189
			[V-10 and A-17 conversion]		190
4F-15	Ac-DWFKAFYDK AAEKFKE VF-NH 2	191
			[conversion D-E]-1-4F-15	Ac- EWFKAFY EKAA DKFK DVF-NH2	192
[conversion D-E]-2-4F-15	Ac- EWFKAFYDKAADKFK EVF-NH2	193
			[conversion D-E]-3-4F-15	Ac-DWFKAFY EKAA DKFKEVF-NH2	194
[conversion D-E]-4-4F-15	Ac-DWFKAFY EKAAEKFK DVF-NH2	195
			[F3 and Y-7 conversion]		196
4F-16	Ac-DW YKAF FDKVAEKFKEAF-NH 2	197
			[conversion D-E]-1-4F-16	Ac- EWYKAFF EKVA DKFK DAF-NH2	198
[conversion D-E]-2-4F-16	Ac- EWYKAFFDKVADKFK EAF-NH2	199
			[conversion D-E]-3-4F-16	Ac-DWYKAFF EKVA DKFKEAF-NH2	200
[conversion D-E]-4-4F-16	Ac-DWYKAFF EKVAEKFK DAF-NH2	201
			[F-3 and V-10 conversion]		202
4F-17	Ac-DW VKAFYDK FAEKFKEAF-NH 2	203
			[conversion D-E]-1-4F-17	Ac- EWVKAFY EKFA DKFK DAF-NH2	204
[conversion D-E]-2-4F-17	Ac- EWVKAFYDKFADKFK EAF-NH2	205
			[conversion D-E]-3-4F-17	Ac-DWVKAFY EKFA DKFKEAF-NH2	206
[conversion D-E]-4-4F-17	Ac-DWVKAFY EKFAEKFK DAF-NH2	207
			[Y-7 and F-14 conversion]		208
4F-18	Ac-DWFKAF FDKVAEK YKEAF-NH 2	209
			[conversion D-E]-1-4F-18	Ac- EWFKAFF EKVA DKYK DAF-NH2	210
[conversion D-E]-2-4F-18	Ac- EWFKAFFDKVADKYK EAF-NH2	211
			[conversion D-E]-3-4F-18	Ac-DWFKAFF EKVA DKYKEAF-NH2	212
[conversion D-E]-3-4F-18	Ac-DWFKAFF EKVA DKYKEAF-NH2	213
			[Y-7 and F-18 conversion]		214
4F-19	Ac-DWFKAF FDKVAEKFKEA Y-NH 2	215

[conversion D-E]-1-4F-19	Ac- EWFKAFF EKVA DKFK DAY-NH2	216
			[conversion D-E]-2-4F-19	Ac- EWFKAFFDKVADKFK EAY-NH2	217
[conversion D-E]-3-4F-19	Ac-DWFKAFF EKVA DKFKEAY-NH2	218
			[conversion D-E]-4-4F-19	Ac-DWFKAFF EKVAEKFK DAY-NH2	219
[V-10 and F-18 conversion]		220
			4F-20	Ac-DWFK4FYDK EAEKFKEA V-NH 2	221
[conversion D-E]-1-4F-20	Ac- EWFKAFY EKFA DKFK DAV-NH2	222
			[conversion D-E]-2-4F-20	Ac- EWFKAFYDKFADKFK EAV-NH2	223
[conversion D-E]-3-4F-20	Ac-DWFKAFY EKFA DKFKEAV-NH2	224
			[conversion D-E]-4-4F-20	Ac-DWFKAFY EKFAEKFK DAV-NH2	225
[W-2 and K13 conversion]		226
			4F-21	Ac-D KFKAFYDKVAEKF WEAF-NH 2	227
[conversion D-E]-1-4F-21	Ac- EKFKAFY EKVA DKFW DAF-NH2	228
			[conversion D-E]-2-4F-21	Ac- EKFKAFYDKVADKFW EAF-NH2	229
[conversion D-E]-3-4F-21	Ac-DKFKAFY EKVA DKFWEAF-NH2	230
			[conversion D-E]-4-4F-21	Ac-DKFKAFY EKVAEKFW DAF-NH2	231
[W-3, F-13 and K-24F]		232
			4F-22	Ac-D KWKAFYDKVAEKF FEAF-NH 2	233
[conversion D-E]-1-4F-22	Ac- EKWKAFY EKVA DKFF DAF-NH2	234
			[conversion D-E]-2-4F-22	Ac- EKWKAFYDKVADKFF EAF-NH2	235
[conversion D-E]-3-4F-22	Ac-DKWKAFY EKVA DKFFEAF-NH2	236
			[conversion D-E]-4-4F-22	Ac-DKWKAFY EKVAEKFF DAF-NH2	237
[K-2，W10，V-13]		238
			4F-23	Ac-D KFKAFYDK WAE VFKEAF-NH 2	239
[conversion D-E]-4F analog		240
			[conversion D-E]-1-4F-23	Ac- EKFKAFY EKWA DVFK DAF-NH2	241
[conversion D-E]-2-4F-23	Ac- EKFKAFYDKWADVFK EAF-NH2	242
			[conversion D-E]-3-4F-23	Ac-DKFKAFY EKWA DVFKEAF-NH2	243
[conversion D-E]-4-4F-23	Ac-DKFKAFY EKWAEVFK DAF-NH2	244
			[K-2，F-13，W-14 4F]		245
4F-24	Ac-D KFKAFYDKVAE FWKEAF-NH 2	246
			[conversion D-E]-4F analog		247
[conversion D-E]-1-4F-24	Ac- EKFKAFY EKVA DFWK DAF-NH2	248
			[conversion D-E]-2-4F-24	Ac- EKFKAFYDKVADFWK EAF-NH2	249
[conversion D-E]-3-4F-24	Ac-DKFKAFY EKVA DFWKEAF-NH2	250
			[conversion D-E]-4-4F-24	Ac-DKFKAFY EKVAEFWK DAF-NH2	251
Reverse 4F analog		252
			Rev-4F	Ac-FAEKFKEAVKDYFAKFWD-NH2	253
[conversion D-E]-1-Rev-4F	Ac-FA DKFK DAVK EYFAKFW E-NH2	254
			[conversion D-E]-2-Rev-4F	Ac-FA DKFKEAVKDYFAKFW E-NH2	255
[conversion D-E]-3-Rev-4F	Ac-FAEKFK DAVK EYFAKFWD-NH2	256
			[conversion D-E]-4-Rev-4F	Ac-FAEKFK DAVKDYFAKFW E-NH2	257
[A-2 and W-17 conversion]		258
			Rev-4F-1	Ac-F WEKFKEAVKDYFAKF AD-NH2	259
[conversion D-E]-1-Rev-4F-1	Ac-FW DKFK DAVK EYFAKFA E-NH2	260
			[conversion D-E]-2-Rev-4F-1	Ac-FA DKFKEAVKDYFAKFW E-NH2	261
[conversion D-E]-3-Rev-4F-1	Ac-FAEKFK DAVK EYFAKFWD-NH2	262
			[conversion D-E]-4-Rev-4F-1	Ac-FAEKFK DAVKDYFAKFW E-NH2	263
[conversion A-2 and F-16]		264
			Rev-4F-2	Ac-F FEKFKEAVKDYF AKAWD-NH2	265
[conversion D-E]-1-Rev-4F-2	Ac-FF DKFK DAVK EYFAKAW E-NH2	266
			[conversion D-E]-2-Rev-4F-2	Ac-FF DKFKEAVKDYFAKAW E-NH2	267
[conversion D-E]-3-Rev-4F-2	Ac-FFEKFK DAVK EYFAKAWD-NH2	268

[conversion D-E]-4-Rev-4F-2	Ac-FFEKFK DAVKDYFAKAW E-NH2	269
			[conversion F-5 and A-8]		270
Rev-4F-3	Ac-FAEK AKE FVKDYFAKFWD-NH2	271
			[conversion D-E]-1-Rev-4F-3	Ac-FA DKAK DFVK EYFAKFW E-NH2	272
[conversion D-E]-2-Rev-4F-3	Ac-FA DKAKEFVKDYFAKFW E-NH2	273
			[conversion D-E]-3-Rev-4F-3	Ac-FAEKAK DFVK EYFAKFWD-NH2	274
[conversion D-E]-4-Rev-4F-3	Ac-FAEKAK DFVKDYFAKFW E-NH2	275
			[conversion A-8 and V9]		276
Rev-4F-4	Ac-FAEKFKE VAKDYFAKFWD-NH2	277
			[conversion D-E]-1-Rev-4F-4	Ac-FA DKFK DVAK EYEAKFW E-NH2	278
[conversion D-E]-2-Rev-4F-4	Ac-FA DKFKEVAKDYFAKFW E-NH2	279
			[conversion D-E]-3-Rev-4F-4	Ac-FAEKFK DVAK EYEAKFWD-NH2	280
[conversion D-E]-4-Rev-4F-4	Ac-FAEKFK DVAKDYFAKFW E-NH2	281
			[conversion V-9 to Y-12]		282
Rev-4F-5	Ac-FAEKFKEA YKD VFAKFWD-NH2	283
			[conversion D-E]-1-Rev-4F-5	Ac-FA DKFK DAYK EVFAKFW E-NH2	284
[conversion D-E]-2-Rev-4F-5	Ac-FA DKFKEAYKDVFAKFW E-NH2	285
			[conversion D-E]-3-Rev-4F-5	Ac-FAEKFK DAYK EVFAKFWD-NH2	286
[conversion D-E]-4-Rev-4F-5	Ac-FAEKFK DAYKDVFAKFW E-NH2	287
			[conversion Y-12 and F-13]		288
Rev-4F-6	Ac-FAEKFKEAVKD FYAKFWD-NH2	289
			[conversion D-E]-1-Rev-4F-6	Ac-FA DKFK DAVK EFYAKFW E-NH2	290
[conversion D-E]-2-Rev-4F-6	Ac-FA DKFKEAVKDFYAKFW E-NH2	291
			[conversion D-E]-3-Rev-4F-6	Ac-FAEKFK DAVK EFYAKFWD-NH2	292
[conversion D-E]-4-Rev-4F-6	Ac-FAEKFK DAVKDFYAKFW E-NH2	293
			[conversion K-6 and W-17]		294
Rev-4F-7	Ac-FAEKF WEAVKDYFAKF KD-NH2	295
			[conversion D-E]-1-Rev-4F-7	Ac-FA DKFW DAVK EYFAKFK E-NH2	296
[conversion D-E]-2-Rev-4F-7	Ac-FA DKFWEAVKDYFAKFK E-NH2	297
			[conversion D-E]-3-Rev-4F-7	Ac-FAEKFW DAVK EYFAKFKD-NH2	298
[conversion D-E]-4-Rev-4F-7	Ac-FAEKFW DAVKDYFAKFK E-NH2	299
			[conversion F-1 and A-2]		300
Rev-4F-8	Ac- AFEKFKEAVKDYFAKFWD-NH2	301
			[conversion D-E]-1-Rev-4F-8	Ac-AF DKFK DAVK EYFAKFW E-NH2	302
[conversion D-E]-2-Rev-4F-8	Ac-AF DKFKEAVKDYFAKFW E-NH2	303
			[conversion D-E]-3-Rev-4F-8	Ac-AFEKFK DAVK EYFAKFWD-NH2	304
[conversion D-E]-4-Rev-4F-8	Ac-AFEKFK DAVKDYFAKFW E-NH2	305
			[F-1 and V-9 change]		306
Rev-F-9	Ac- VAEKFKEA FKDYFAKFWD-NH2	307
			[conversion D-E]-1-Rev-4F-9	Ac-VA DKFK DAFK EYFAKFW E-NH2	308
[conversion D-E]-2-Rev-4F-9	Ac-VA DKFKEAFKDYFAKFW E-NH2	309
			[conversion D-E]-3-Rev-4F-9	Ac-VAEKFK DAFK EYFAKFWD-NH2	310
[conversion D-E]-4-Rev-4F-9	Ac-VAEKFK DAFKDYFAKFW E-NH2	311
			[F-1 and Y-12 change]		312
Rev-4F-10	Ac- YAEKFKEAVKD FFAKFWD-NH2	313
			[conversion D-E]-1-Rev-4F-10	Ac-YA DKFK DAVK EFFAKFW E-NH2	314
[conversion D-E]-2-Rev-4F-10	Ac-YA DKFKEAVKDFFAKFW E-NH2	315
			[conversion D-E]-3-Rev-4F-10	Ac-YAEKFK DAVK EFFAKFWD-NH2	316
[conversion D-E]-4-Rev-4F-10	Ac-YAEKFK DAVKDFFAKFW E-NH2	317
			[F-1 and A-8 change]		318
Rev-4F-11	Ac- AAEKFKE FVKDYFAKFWD-NH2	319
			[conversion D-E]-1-Rev-4F-11	Ac-AA DKFK DFVK EYFAKFW E-NH2	320
[conversion D-E]-2-Rev-4F-11	Ac-AA DKFKEFVKDYFAKFW E-NH2	321

[conversion D-E]-3-Rev-4F-11	Ac-AAEKFK DFVK EYFAKFWD-NH2	322
			[conversion D-E]-4-Rev-4F-11	Ac-AAEKFK DFVKDYFAKFW E-NH2	323
[A-2 and F-5 change]		324
			Rev-4F-12	Ac-F FEK AKEAVKDYFAKFWD-NH2	325
[conversion D-E]-1-Rev-4F-12	Ac-FF DKAK DAVK EYFAKFW E-NH2	326
			[conversion D-E]-2-Rev-4F-12	Ac-FF DKAKEAVKDYFAKFW E-NH2	327
[conversion D-E]-3-Rev-4F-12	Ac-FFEKAK DAVK EYFAKFWD-NH2	328
			[conversion D-E]-4-Rev-4F-12	Ac-FFEKAK DAVKDYFAKFW E-NH2	329
[A-2 and Y12 change]		330
			Rev-4F-13	Ac-F YEKFKEAVKD AFAKFWD-NH2	331
[conversion D-E]-1-Rev-4F-13	Ac-FY DKFK DAVK EAFAKFW E-NH2	332
			[conversion D-E]-2-Rev-4F-13	Ac-FY DKFKEAVKDAFAKFW E-NH2	333
[conversion D-E]-3-Rev-4F-13	Ac-FYEKFK DAVK EAFAKFWD-NH2	334
			[conversion D-E]-4-Rev-4F-13	Ac-FYEKFK DAVKDAFAKFW E-NH2	335
[A-2 and V-9 change]		336
			Rev-4F-14	Ac-F VEKFKEA AKDYFAKFWD-NH2	337
[conversion D-E]-1-Rev-4F-14	Ac-FV DKFK DAAK EYFAKFW E-NH2	338
			[conversion D-E]-2-Rev-4F-14	Ac-FV DKFKEAAKDYFAKFW E-NH2	339
[conversion D-E]-3-Rev-4F-14	Ac-FVEKFK DAAK EYKAKFWD-NH2	340
			[conversion D-E]-4-Rev-4F-14	Ac-FVEKFK DAAKDYFAKFW E-NH2	341
[F-5 and Y-12 change]		342
			Rev-4F-15	Ac-FAEK YKEAVKD FFAKFWD-NH2	343
[conversion D-E]-1-Rev-4F-15	Ac-FA DKYK DAVK EFFAKFW E-NH2	344
			[conversion D-E]-2-Rev-4F-15	Ac-FA DKYKEAVKDFFAKFW E-NH2	345
[conversion D-E]-3-Rev-4F-15	Ac-FAEKYK DAVK EFFAKFWD-NH2	346
			[conversion D-E]-4-Rev-4F-15	Ac-FAEKYK DAVKDFFAKFW E-NH2	347
[F-5 and V-9 change]		348
			Rev-4F-16	Ac-FAEK VKEA FKDYFAKFWD-NH2	349
[conversion D-E]-1-Rev-4F-16	Ac-FA DKVK DAFK EYFAKFW E-NH2	350
			[conversion D-E]-2-Rev-4F-16	Ac-FA DKVKEAFKDYFAKFW E-NH2	351
[conversion D-E]-3-Rev-4F-16	Ac-FAEKVK DAFK EYFAKFWD-NH2	352
			[conversion D-E]-4-Rev-4F-16	Ac-FAEKVK DAFKDYFAKFW E-NH2	353
[A-8 and Y-12 conversion]		354
			Rev-4F-17	Ac-FAEKFKE YVKD AFAKFWD-NH2	355
[conversion D-E]-1-Rev-4F-17	Ac-FA DKFK DYVK EAFAKFW E-NH2	356
			[conversion D-E]-2-Rev-4F-17	Ac-FA DKFKEYVKDAFAKFW E-NH2	357
[conversion D-E]-3-Rev-4F-17	Ac-FAWKFK DYVK EAFAKFWD-NH2	358
			[conversion D-E]-4-Rev-4F-17	Ac-FAEKFK DYVKDAFAKFW E-NH2	359
[V-9 and F-13 change]		360
			Rev-4F-18	Ac-FAEKFKEA FKDY VAKFWD-NH2	361
[conversion D-E]-1-Rev-4F-18	Ac-FA DKFK DAFK EYVAKFW E-NH2	362
			[conversion D-E]-2-Rev-4F-18	Ac-FA DKFKEAFKDYVAKFW E-NH2	363
[conversion D-E]-3-Rev-4F-18	Ac-FAEKFK DAFK EYVAKFWD-NH2	364
			[conversion D-E]-4-Rev-4F-18	Ac-FAEKFK DAFKDYVAKFW E-NH2	365
[V-9 and F-16 conversion]		366
			Rev-4F-19	Ac-FAEKFKEA FKDYFAK VWD-NH2	367
[conversion D-E]-1-Rev-4F-19	Ac-FA DKFK DAFK EYFAKVW E-NH2	368
			[conversion D-E]-2-Rev-4F-19	Ac-FA DKFKEAFKDYFAKVW E-NH2	369
[conversion D-E]-3-Rev-4F-19	Ac-FAEKFK DAFK EYFAKVWD-NH2	370
			[conversion D-E]-4-Rev-4F-19	Ac-FAEKFK DAFKDYFAKVW E-NH2	371
[Y-12 and F-16 change]		372
			Rev-4F-20	Ac-FAEKFKEAVKD FFAK YWD-NH2	373
[conversion D-E]-1-Rev-4F-20	Ac-FA DKFK DAVK EFFAKYW E-NH2	374

[conversion D-E]-2-Rev-4F-20	Ac-FA DKFKEAVKDFFAKYW E-NH2	375
			[conversion D-E]-3-Rev-4F-20	Ac-FAEKFK DAVK EFFAKYWD-NH2	376
[conversion D-E]-4-Rev-4F-20	Ac-FAEKFK DAVKDFFAKYW E-NH2	377
			[W-1, F-6 and K-17 Rev 4F]		378
Rev-4F-21	Ac- WAEK FFEAVKDYFAKF KD-NH2	379
			[conversion D-E]-1-Rev-4F-7	Ac-WA DKFF DAVK EYFAKFK E-NH2	380
[conversion D-E]-2-Rev-4F-7	Ac-WA DKFFEAVKDYFAKFK E-NH2	381
			[conversion D-E]-3-Rev-4F-7	Ac-WAEKFF DAVK EYFAKFKD-NH2	382
[conversion D-E]-4-Rev-4F-7	Ac-WAEKFF DAVKDYFAKFK E-NH2	383
			[W-5, F-6 and K-17 Rev-4F]		384
Rev-4F-22	Ac-FAEK WFEAVKDYFAKF KD-NH2	385
			[conversion D-E]-1-Rev-4F-22	Ac-FA DKWF DAVK EYFAKFK E-NH2	386
[conversion D-E]-2-Rev-4F-22	Ac-FA DKWFEAVKDYFAKFK E-NH2	387
			[conversion D-E]-3-Rev-4F-22	Ac-FAEKWF DAVK EYFAKFKD-NH2	388
[conversion D-E]-4-Rev-4F-22	Ac-FAEKWF DAVKDYFAKFK E-NH2	389
			[V-6，W-9，K-17 Rev-4F]		390
Rev-4F-23	Ac-FAEKF VEA WKDYFAKF KD-NH2	391
			[conversion D-E]-1-Rev-4F-23	Ac-FA DKFV DAWK EYFAKFK E-NH2	392
[conversion D-E]-2-Rev-4F-23	Ac-FA DKFVEAWKDYFAKFK E-NH2	393
			[conversion D-E]-3-Rev-4F-23	Ac-FAEKFV DAWK EYFAKFKD-NH2	394
[conversion D-E]-4-Rev-4F-23	Ac-FAEKFV DAWKDYFAKFK E-NH2	395
			[Y-2，A-4，W-12，K-17 Rev-4F]		396
Rev-4F-24	Ac-F YEKF AEAVKD WFAKF KD-NH2	397
			[conversion D-E]-1-Rev-4F-24	Ac-FY DKFA DAVK EWFAKFK E-NH2	398
[conversion D-E]-2-Rev-4F-24	Ac-FY DKFAEAVKDWFAKFK E-NH2	399
			[conversion D-E]-3-Rev-4F-24	Ac-FYEKFA DAVK EWFAKFKD-NH2	400
[conversion D-E]-4-Rev-4F-24	Ac-FYEKFA DAVKDWFAKFK E-NH2	401

[0130] according to spiral colyliform figure shown in Figure 15, may easily identify biological activity and useful peptide.For example, following peptide has been activated by clearly identifying: reverse (reverse) form of 3F1,3F2,4F and its reverse contrary type form.Therefore, in certain embodiments, the present invention includes activating agent, comprising length is 18 aminoacid and the peptide that forms the category-A amphipathic helix, wherein the aminoacid of peptide consists of 2 aspartic acids, 2 glutamic acid, 4 lysines, 1 tryptophan, 1 tyrosine, be no more than 1 leucine, be no more than 1 valine, alanine more than 1 below 3 and 3-6 is selected from following aminoacid: phenylalanine, α-naphthylalanine, β-naphthylalanine, histidine, and contain 9 or 10 aminoacid on the polar surface of the spiral colyliform figure of category-A amphipathic helix, be included in 4 positively charged under neutral pH aminoacid, wherein 2 positively charged residues are positioned at the interface of polarity and non-polar plane, there are 2 to be present on the polar surface continuously in 4 positively charged residues, 2 amino acid residues on the non-polar plane are selected from: phenylalanine, α-naphthylalanine, β-naphthylalanine, histidine, equally also be successive, if in this group 4 or amino acids are more arranged on the non-polar plane, then at least 2 residues of this group are discontinuous.

[0131] in certain embodiments, the present invention also comprises some Y class amphipathic helix peptide and category-A amphipathic helix peptide.Y class amphipathic helix peptide is known to those skilled in the art (referring to (1992) J.Lipid Res.33:141-166 such as for example SeGRest; Oram and Heinecke (2005) Physiol Rev.85:1343-1372 etc.).In different embodiments, these peptides include but not limited to form 18 amino acid peptides of category-A amphipathic helix or the described Y class amphipathic helix of Formula Il I (SEQ IDNO:402):

D X X K Y X X D K X Y D KX K D Y X III

Wherein D is Asp or Glu independently; K is Lys or Arg independently; X is Leu, norLeu, Val, Ile, Trp, Phe, Tyr, β-Nal or α-Nal independently, all X residues all on non-polar plane, except that 1 can be between 2 K residues of polar surface when spiral colyliform figure observes (for example when from); Y independently for Ala, His, Ser, Gln, Asn or Thr when spiral colyliform figure observes (for example when from) on the non-polar plane, and Y is 1 Ala on the polar surface independently, 1 His, 1 Ser, 1 Gln, 1 Asn or 1 Thr be when spiral colyliform figure observes (for example when from) on the polar surface, wherein is no more than 2 K and is successive when spiral colyliform figure observes (for example when from); Wherein be no more than 3 D and be successive when spiral colyliform figure observes (for example when from), and the 4th D separated by Y and other D.The exemplary peptides that this class includes the peptide of histidine and/or α-naphthylalanine and/or β-naphthylalanine sees Table 5.In the form that reverse (reverse) of these peptides, contrary type, reverse contrary type and sequence cycles change is also included within.

[0132] table 5. expression His joins various category-As and/or the Y class peptide analogues in the sequence.

Be called for short Peptide sequence SEQ

ID

NO

[A-5＞H]4F Ac-DWFK HFYDKVAEKFKEAF-NH ₂ 403

[A-5＞H, the D-E conversion] 4F Ac- EWFK HFY EKVA DKFK DAF-NH ₂404

[A-5＞H，D-1＞E]4F Ac- EWFK HFYDKVAEKFKEAF-NH ₂ 405

[A-5＞H，D-8＞E]4-F Ac-DWFK HFY EKVAEKFKEAF-NH ₂ 406

[A-5＞H，E-12＞D]4F Ac-DWFK HFYDKVA DKFKEAF-NH ₂ 407

[A-5＞H，E-16＞D]4F Ac-DWFK HFYDKVAEKFK DAF-NH ₂ 408

[F-3＞H，A-5＞F]-4F Ac-DW HK FFYDKVAEKFKEAF-NH 2 409

[F-3＞H, A-5＞F, the D-E conversion]-4F Ac- EW HK FFY EKVA DKFK DAF-NH ₂410

[F-3＞H，A-5＞F，D-1＞E]-4F Ac- EW HK FFYDKVAEKFKEAF-NH ₂ 411

[F-3＞H，A-5＞F，D-8＞E]-4F Ac-DW HK FFYEKVA DKFKEAF-NH ₂ 412

[F-3＞H，A-5＞F，E-12＞D]-4F Ac-DW HK FFYDKVA DKFKEAF-NH ₂ 413

[F-3＞H，A-5＞F，E-16＞D]-4F Ac-DW HK FFYDKVAEKFK DAF-NH ₂ 414

[A-5＞F，F-6＞H]4F Ac-DWFK FHYDKVAEKFKEAF-NH ₂ 415

[A-5＞F, F-6＞H, the D-E conversion] 4F Ac- EWFK FHYEKVA DKFK DAF-NH ₂416

[[A-5＞F，F-6＞H，D-1＞E]4F Ac- EWFK FHYDKVAEKFKEAF-NH ₂ 417

[A-5＞F，F-6＞H，D-8＞E]4F Ac-DW FHFHY EKVAEKFKEAF-NH ₂ 418

[A-5＞F，F-6＞H，E-12＞D]4F Ac-DW FHFHYDKVA DKFKEAF-NH ₂ 419

[A-5＞F，F-6＞H，E-16＞D]4F Ac-DW FHFHYDKVAEKFK DAF-NH ₂ 420

[A-5＞V，V-10＞H]4F Ac-DWFK VFYDK HAEKFKEAF-NH ₂ 421

[A-5＞V, V-10＞H, the D-E conversion] 4F Ac- EWFK VFY EK HA DKFK DAF-NH ₂422

[A-5＞V，V-10＞H，D-1＞E]4F Ac- EWFK VFYDK HAEKFKEAF-NH ₂ 423

[A-5＞V，V-10＞H，D-8＞E]4F Ac-DWFK VFY EK HAEKFKEAF-NH ₂ 424

[A-5＞V，V-10＞H，E-12＞D]4F Ac-DWFK VFYDK HA DKFKEAF-NH ₂ 425

[A-5＞V，V-10＞H，E16＞D]4F Ac-DWFK VFYDK HAEKFK DAF-NH ₂ 426

[[A-17＞H]4F Ac-DWFKAFYDKVAEKFKE HF-NH ₂ 427

[A-17＞H, the D-E conversion] 4F Ac- EWFKAFY EKVA DKFK DHF-NH ₂428

[[A-17＞H，D-1＞E]4F Ac- EWFKAFYDKVAEKFKE HF-NH ₂ 429

[[A-17＞H，D-8＞E]4F Ac-DWFKAFY EKVAEKFKE HF-NH ₂ 430

[[A-17＞H，E-12＞D]4F Ac-DWFKAFYDKVA DKFKE HF-NH ₂ 431

[[A-17＞H，E16＞D]4F Ac-DWFKAFYDKVAEKFK DHF-NH ₂ 432

[A-17＞F，F-18＞H]4F Ac-DWFKAFYDKVAEKFKE FH-NH ₂ 433

[A-17＞F, F-18＞H, the D-E conversion] 4F Ac- EWFKAFY EKVA DKFK DFH-NH ₂434

[A-17＞F，F-18＞H，D-1＞E]-4F Ac- EWFKAFYDKVAEKFKE FH-NH ₂ 435

[A-17＞F，F-18＞H]4F Ac-DWFKAFYDKVAEKFKE FH-NH ₂ 436

[A-17＞F，F-18＞H，D-8＞E]-4F Ac-DWFKAFY EKVAEKFKE FH-NH ₂ 437

[A-17＞F，F-18＞H，E-12＞D]4F Ac-DWFKAFYDKVAEKFKE FH-NH ₂ 438

[A-17＞F，F-18＞H]，E-16＞D]-4F Ac-DWFKAFYDKVAEKFK DFH-NH ₂ 439

Rev-4F Ac-FAEKFKEAVKDYFAKFWD-NH ₂ 440

[A-2＞H]Rev4F Ac-F HEKFKEAVKDYFAKFWD-NH ₂ 441

Rev-[A-2＞H，D＞E]-4F Ac-FE HFKEAK EAEYFAKFW E-NH ₂ 442

Rev-[A-2＞H，E＞D]4F Ac-F HDKFK DAVKDYFAKFWD-NH ₂ 443

[A-2＞H, the D-E conversion] Rev-4F Ac-F HDKFKDAVK EYFAKFW E-NH ₂444

[A-2＞H，E-3＞D]Rev-4F Ac-F HDKFKEAVKDYFAKFWD-NH ₂ 445

[A-2＞H，E-7＞D]Rev-4F Ac-F HEKFKDAVKDYFAKFWD-NH ₂ 446

[A-2＞H，D-11＞E]Rev-4F Ac-F HEKFKEAVK EYFAKFWD-NH ₂ 447

[A-2＞H，D-18＞E]Rev-4F Ac-F HEKFKEAVKDYFAKFW E-NH ₂ 448

[F-1＞H，A-2＞F]Rev-4F Ac- HFEKFKEAVKDYFAKFWD-NH ₂ 449

[F-1＞H, A-2＞F, the D-E conversion] Rev-Ac- HFDKFK DAVK EYFAKFW E-NH ₂450

4F

[F-1＞H，A-2＞F，D＞E]Rev-4F Ac- HFEKFKEAVK EYFAKFWE-NH ₂ 451

[F-1＞H，A-2＞F，E-3＞D]Rev-4F Ac- HFDKFKEAVKDYKAKFWD-NH ₂ 452

[F-1＞H，A-2＞F，E-7＞D]Rev-4F Ac- HFKEFK DAVKDYFAKFWD-NH ₂ 453

[F-1＞H，A-2＞F，D-11＞E]Rev-4F Ac- HFEKFKEAVK EYFAKFWD-NH ₂ 454

[F-1＞H，A-2＞F，D-18＞E]Rev-4F Ac- HFEKFKEAVKDYFAKFW E-NH ₂ 455

[A-2＞F，F-5＞E]Rev D-4F Ac-F FEK HKEAVKDYFAKFWD-NH ₂ 456

[A-2＞F, F-5＞H, the D-E conversion] Rev Ac-F FDK HK DAVK EYKAKFW E-NH ₂457

D-4F

[A-2＞F，F-5＞H，D＞E]Rev D-4F Ac-F FEK HKEAVK EYFAKFW E-NH ₂ 458

[A-2＞F，F-5＞H，E＞D]Rev D-4F Ac-F FDK HK DAVKDYFAKFWD-NH ₂ 459

[A-2＞F，F-5＞H，E-3＞D]Rev D-4F Ac-F FDK HKEAVKDYFAKFWD-NH ₂ 460

[A-2＞F，F-5＞H，D-11＞E]Rev D-4F Ac-F FEK HK EAVK EYFAKFWD-NH ₂ 461

[A-2＞F，F-5＞H，D-18＞E]Rev D-4F Ac-F FEK HKEAVKDYFAKFW E-NH ₂ 462

[A-2＞V，V-9＞E]Rev D-4F Ac-F VEKEKEA HKDYFAKFWD-NH ₂ 463

[A-2＞V, V-9＞H, the D-E conversion] Rev Ac-F VDKFK DA HK EYFAKFW E-NH ₂464

D-4F

[A-2＞V，V-9＞H，D＞E]Rev D-4F Ac-F VEKFKEA HK EYFAKFW E-NH ₂ 465

[a-2＞V，V-9＞H，E＞D]Rev D-4F Ac-F VDKFK DA HKDYFAKFWD-NH ₂ 466

[A-2＞V，V-9＞H，E-3＞D]Rev D-4F Ac-F VDKFKEA HKDYFAKFWD-NH ₂ 467

[A-2＞V，V-9＞H，E-7＞D]Rev D-4F Ac-F VEKFK DA HKDYFAKFWD-NH ₂ 468

[A-2＞V，V-9＞H，D-11＞E]Rev D-4F Ac-F VEKFKEA HK EYFAKFWD-NH ₂ 469

[A-2＞V，V-9＞H，D-18＞E]Rev D-4F Ac-F VEKFKEA HKDYFAKFW E-NH ₂ 470

[A-8＞H]Rev-4F Ac-FAEKFKE HVKDYFAKFWD-NH ₂ 471

[A-8＞H, the D-E conversion] Rev-4F Ac-FA DKFK DHVK EYFAKFW E-NH ₂472

[A-8＞H，D＞E]Rev-4F Ac-FAEKFKE HVK EYFAKFWE-NH ₂ 473

[A-8＞H，E＞D]Rev-4F Ac-FA DKFK DHVKDYFAKFWD-NH ₂ 474

[A-8＞H，E-3＞D]Rev-4F Ac-FA DKFKE HVKDYFAKFWD-NH ₂ 475

[A-8＞H，E-7＞D]Rev-4F Ac-FAEKFK DHVKDYFAKFWD-NH ₂ 476

[A-8＞H，D-11＞E]Rev-4F Ac-FAEKFKE HVK EYFAKFWD-NH ₂ 477

[A-8＞H，D-18＞E]Rev-4F Ac-FAEKFKE HVKDYFAKFW E-NH ₂ 478

[A-8＞F，F-13＞H]Rev-4F Ac-FAEKFKE FVKDY HAKFWD-NH ₂ 479

[A-8＞F, F-13＞H, the D-E conversion] Rev-Ac-FA DKFK DFVK EY HAKFW E-NH ₂480

4F

[A-8＞F，F-13＞H，E-3＞D]Rev-4F Ac-FA DKFKE FVKDY HAKFWD-NH ₂ 481

[A-8＞F，F-13＞H，E-7＞D]Rev-4F Ac-FAEKFK DFVKDY HAKFWD-NH ₂ 482

[A-8＞F，F-13＞H，E＞D]Rev-4F Ae-FA DKFK DFVKDY HAKFWD-NH ₂ 483

[A-8＞F，F-13＞H，D＞E]Rev-4F Ac-FAEKFKE FVK EY HAKFW E-NH ₂ 484

[A-8＞F，F-13＞H，D-11＞E]Rev-4F Ac-FAEKFKE FVK EY HAKFWD-NH ₂ 485

[A-8＞F，F-13＞H，D-18＞E]Rev-4F Ac-FAEKF FKEVKDY HAKFW E-NH ₂ 486

[A-8＞F，F16＞H]Rev.-4F Ac-FAEKFKE FVKDYFAK HWD-NH ₂ 487

[A-8＞F，F16＞H，D-E Ac-FA DKFK DFVK EYFAK HW E-NH ₂ 488

[the Rev.-4F of conversion

[A-8＞F，F16＞H，D＞E]Rev.-4F Ac-FAEKFKE FVK EYFAK HW E-NH ₂ 489

[A-8＞F，F16＞H，E＞D]Rev.-4F Ac-FA DKFK DFVKDYFAK HWD-NH ₂ 490

[A-8＞F，F16＞H，E-3＞D]Rev.-4F Ac-FA DKFKE FVKDYFAK HWD-NH ₂ 491

[A-8＞F，F16＞H，E-7＞D]Rev.-4F Ac-FAEKFK DFVKDYFAK HWD-NH ₂ 492

[A-8＞F，F16＞H，D-11＞E]Rev.-4F Ac-FAEKFKE FVK EYFAK HWD-NH ₂ 493

[A-8＞F，F16＞H，D-18＞E]Rev.-4F Ac-FAEKFKE FVKDYFAK HW E-NH ₂ 494

Have the category-A 4F of β-Nph and the example of Rev 4F analog.Similarly, can design α-Nph analog.Thing similar to the above is similar, His can be incorporated in the Nph analog.D＞E analog, E＞D analog also is that the similar another kind of thing similar to the above may with D-E conversion analog.

E4Nph Ac-DW NphKA NphYDKVAEK NphKEA Nph-NH2 495

[the D-E conversion] 4Nph Ac- EW NphKA NphY EKVA DK NphK DA Nph-NH2 496

[D＞E]4Nph Ac- EW NphKA NphY EKVAEK NphKEA Nph-NH2 497

[E＞D]4Nph Ac-DW NphKA NphYDKVA DK NphKDA Nph-NH2 498

[D-1＞E]4Nph Ac- EW NphKA NphYDKVAEK NphKEA Nph-NH2 499

[D-8＞E]4Nph Ac-DW NphKA NphY EKVAEK NphKEA Nph-NH2 500

[E-12＞D]4Nph Ac-DW NphKA NphYDKVA DK NphKEA Nph-NH2 501

[E-16＞D]4Nph Ac-DW NphKA NphYDKVAEK NphK DA Nph-NH2 502

For 4Nph, minimum 7 extra analog of each analog are as follows as mentioned above.

[F-3，6，＞Nph]4F Ac-DW NphKA NphYDKVAEKFKEAF-NH2 503

[F-14，18＞Nph]4F Ac-DWFKAFYDKVAEK NphKEA Nph-NH2 504

[[F-3＞Nph]4F Ac-DW NphKAFYDKVAEKFKEAF-NH2 505

[F-6＞Nph]4F Ac-DWFKA NphYDKVAEKFKEAF-NH2 506

[F-14＞Nph]4F Ac-DWFKAFYDKVAEK NphKEAF-NH2 507

[F-18＞Nph]4F Ac-DWFKAFYDKVAEKFKEA Nph-NH2 508

For following each analog, by conversion D-E, D＞E and E＞D and single D or E analog, minimum as mentioned above 7 extra analog are possible.

Rev-4Nph Ac- NphAEK NphKEAVKDY NphAK NphWD-NH2 509

[F-3，6＞Nph]Rev 4F Ac- NphAEK NphKEAVKDYFAKFWD-NH2 510

[F-13，16]Rev-4F Ac-FAEKFKEAVKDY NphAK NphWD-NH2 511

[F-3＞Nph]Rev-4F Ac- NphAEKFKEAVKDYFAKFWD-NH2 512

[F-6＞Nph]Rev-4F Ac-FAEK NphKEAVKDYFAKFWD-NH2 513

[F-13＞Nph]Rev-4F Ac-FAEKFKEAVKDY NphAKFWD-NH2 514

[F-16＞Nph]Rev-4F Ac-FAEKFKEAVKDYFAK NphWD-NH2 515

For following analog, by mixing His or α-Nph and β-Nph, extra analog is possible.

Rev-[D＞E]-4F Ac-FAEKFKEAVK EYFAKFW E-NH2 516

Rev-[E＞D]4F Ac-FA DKFK DAVKDYFAKFWD-NH2 517

Rev-R4-4F Ac-FAE RFREAVKDYFAKFWD-NH2 518

Rev-R6-4F Ac-FAEKF REAVKDYFAKFWD-NH2 519

Rev-R10-4F Ac-FAEKFKEAV RDYFAKFWD-NH2 520

Rev-R14-4F Ac-FAEKFKEAVKDYFA RFWD-NH2 521

Rev-[D＞E]-4F Ac-FAEKFKEAVK EYFAKFW E-NH2 522

Rev-[E＞D]4F Ac-FA DKFK DAVKDYFAKFWD-NH2 523

Rev-R4-4F Ac-FAE RFREAVKDYFAKFWD-NH2 524

Rev-R6-4F Ac-FAEKF REAVKDYFAKFWD-NH2 525

Rev-R10-4F Ac-FAEKFKEAV RDYFAKFWD-NH2 526

Rev-R14-4F Ac-FAFKFKEAVKDYFA RFWD-NH2 527

Rev-[D＞E]-4F Ac-FAEKFKEAVK EYFAKFW E-NH2 528

Rev-[E＞D]4F Ac-FA DKFK DAVKDYFAKFWD-NH2 529

Rev-R4-4F Ac-FAE RFREAVKDYFAKFWD-NH2 530

Rev-R6-4F Ac-FAEKF REAVKDYFAKFWD-NH2 531

Rev-R10-4F Ac-FAEKFKEAV RDYFAKFWD-NH2 532

Rev-R14-4F Ac-FAEKFKEAVKDYFA RFWD-NH2 533

Rev-R4-4F Ac-FAE RFREAVKDYFAKFWD-NH2 534

Rev-R6-4F Ac-FAEKF REAVKDYFAKFWD-NH2 535

Rev-R10-4F Ac-FAEKFKEAV RDYFAKFWD-NH2 536

Rev-R14-4F Ac-FAEKFKEAVKDYFA RFWD-NH2 537

Rev-[D＞E]-4F Ac-FAEKFKEAVK EYFAKFW E-NH2 538

Rev-[E＞D]4F Ac-FA DKFK DAVKDYFAKFWD-NH2 539

Rev-R4-4F Ac-FAE RFREAVKDYFAKFWD-NH2 540

Rev-R6-4F Ac-FAEKF REAVKDYFAKFWD-NH2 541

Rev-R10-4F Ac-FAEKFKEAV RDYFAKFWD-NH2 542

Rev-R14-4F Ac-FAEKFKEAVKDYFA RFWD-NH2 543

For following analog, use above-mentioned example, extra H and Nph analog are possible.With the variation in the above-mentioned example, each analog can obtain 7 analog.

Rev3F-2 Ac-LFEKFAEAFKDYVAKWKD-NH2 544

RevR4-3F-2 Ac-LFE RFAEAFKDYVAKWKD-NH2 545

RevR10-3F2 Ac-LFEKFAEAF RDYVAKWKD-NH2 546

RevR15-3F-2 Ac-LFEKFAEAFKDYVA RWKD-NH2 547

RevR17-3F-2 Ac-LFEKFAEAFKDYVAKW RD-NH2 548

Rev[D＞E]3F-2 Ac-LFEKFAEAFK EYVAKWK E-NH2 549

Rev[E3＞D]3F-2 Ac-LF DKFA DAFKDYVAKWKD-NH2 550

Rev[E7＞D]-3F-2 Ac-LF DKFAEAFKDYVAKWKD-NH2 551

Rev[E7＞D]3F-2 Ac-LFEKFA DAFKDYVAKWKD-NH2 552

Rev[D11＞E]3F-2 Ac-LFEKFAEAFK EYVAKWKD-NH2 553

Rev-[D18＞E]3F-2 Ac-LFEKFAEAFKDYVAKWK E-NH2 554

Rev3F-1 Ac-FAEKAWEFVKDYFAKLKD-NH2 555

RevR4-3F-1 Ac-FAE RAWEFVKDYFAKLKD-NH2 556

RevR10-3F-1 Ac-FAEKAWEFV KDYFAKLKD-NH2 557

RevR15-3F-1 Ac-FAEKAWEFVKDYFA KLKD-NH2 558

RevR17-3F-1 Ac-FAEKAWEFVKDYFAKL RD-NH2 559

Rev[D＞E]3F-1 Ac-FAEKAWEFVK EYFAKLK E-NH2 560

Rev[E＞D]3F-1 Ac-FA DKAW DFVKDYFAKLKD-NH2 561

Rev[E3＞D]-3F-1 Ac-FA DKAWEFVKDYFAKLKD-NH2 562

Rev[E7＞D]3F-1 Ac-FAEKAW DFVKDYFAKLKD-NH2 563

Rev-[D11＞E]3F-1 Ac-FAEKAWEFVK EYFAKLKD-NH2 564

Rev-[D18＞E]3F-1 Ac-FAEKAWEFVKDYFAKLK E-NH2 565

Rev-5F Ac-FFEKFKEFVKDYFAKLWD-NH2 566

Rev-[D＞E]5F Ac-FFEKFKEFVK EYFAKLW E-NH2 567

Rev-[E＞D]5F Ac-FF DKFK DFVKDYFAKLWD-NH2 568

Rev-R4-5F Ac-FFE RFKEFVKDYFAKLWD-NH2 569

Rev-R6-5F Ac-FFEKF REFVKDYFAKLWD-NH2 570

Rev-R10-5F Ac-FFEKFKEFV RDYFAKLWD-NH2 571

Rev-R15-5F Ac-FFEKFKEFVKDYFA RLWD-NH2 572

Rev-[E3＞D]-5F Ac-FF DKFKEFVKDYFAKLWD-NH2 573

Rev-[E7＞D]5F Ac-FFEKFK DFVKDYFAKLWD-NH2 574

Rev-[D11＞E]-5F Ac-FFEKFKEFVK EYFAKLWD-NH2 575

Rev-[D18＞E]-5F Ac-FFEKFKEFVKDYFAKLW E-NH2 576

Rev-5F-2 Ac-F LEFKKEFVKDY FAKFWD-NH2 577

Rev-[D＞E]-5F-2 Ac-FLEKFKEFVK EYFAKFW E-NH2 578

Rev-[E＞D]-5F-2 Ac-FL DKFK EFVKDYFAKFWD-NH2 579

Rev-[E3＞D]-5F-2 Ac-FL DKFKEFVKDYFAKFWD-NH2 580

Rev-[E7＞D]-5F-2 Ac-FLEKFK DFVKDYFAKFWD-NH2 581

Rev-[D11＞E]-5F-2 Ac-FLEKFKEFVK EYFAKFWD-NH2 582

REv-[D18＞E]-5F-2 Ac-FLEKFKEFVKDYFAKFW E-NH2 583

Rev-R4-5F-2 Ac-FLE RFKEFVKDYFAKFWD-NH2 584

Rev-R6-5F-2 Ac-FLEKF REFVKDYFAKFWD-NH2 585

RevR10-5F-2 Ac-FLEKFKEFV RDYFAKFWD-NH2 586

Rev-R16-5F-2 Ac-FLEKFKEFVKDYFA RFWD-NH2 587

Rev-6F Ac-F FEK FKE FFKDYFAKLWD-NH2 588

Rev-[D＞E]-6F Ac-FFEKFKEFFK EYFAKLW E-NH2 589

Rev-[E＞D]-6F Ac-FF DKFK DFFKDYFAKLWD-NH2 590

Rev-R4-6F Ac-FFE RFKEFFKDYFAKLWD-NH2 591

Rev-R6-6F Ac-FFEKF REFFKDYFAKLWD-NH2 592

Rev-R10-6F Ac-F FEKFKEFF RDYFAKLWD-NH2 593

Rev-R14-6F Ac-FFERFKEFFKDYFA RLWD-NH2 594

Rev-[E3＞D]-6F Ac-FF DKFKEFFKDYFAKLWD-NH2 595

Rev-[E7＞D]-6F Ac-FFEKFK DFFKDYFAKLWD-NH2 596

Rev-[D11＞E]-6F Ac-FFEKFKEFFK EYFAKLWD-NH2 597

Rev-[D18＞E]-6F Ac-FFEKFKEFFKDYFAKLW E-NH2 598

Rev-4F Ac-FAEKFKEAVKDYFAKFWD-NH2 599

Rev-[D＞E]-4F Ac-FAEKFKEAVK EYFAKFW E-NH2 600

Rev-[E＞D]4F Ac-FA DKFK DAVKDYFAKFWD-NH2 601

Rev-R4-4F Ac-FAE RFREAVKDYFAKFWD-NH2 602

Rev-R6-4F Ac-FAEKF REAVKDYFAKFWD-NH2 603

Rev-R10-4F Ac-FAEKFKEAV RDYFAKFWD-NH2 604

Rev-R14-4F Ac-FAEKFKEAVKDYFA RFWD-NH2 605

4F-2 Ac-DKWKAVYDKFAEAFKEFF-NH2 606

[D＞E]-4F-2 Ac-EKWKAVYEKFAEAFKEFF-NH2 607

[E＞D]-4F-2 Ac-DKWKAVYDKFA DAFK DFF-NH2 608

R2-4F-2 Ac-D RWKAVYDKFAEAFKEEF-NH2 609

R4-4F-2 Ac-DKW RAVYDKFAEAFKEFF-NH2 610

R9-4F-2 Ac-DKWKAVYD RFAEAFKEFF-NH2 611

R14-4F-2 Ac-DKWKAVYDKFAEAF REFF-NH2 612

Rev4F-2 Ac-FFEKFAEAFKDYVAKWKD-NH2 613

Rev-[D＞E]-4F-2 Ac-FFEKFAEAFK EYVAKWK E-NH2 614

Rev-[E＞D]-3F-2 Ac-FF DKFA DAFKDYVAKWKD-NH2 615

Rev-R4-4F-2 Ac-FFE RFAEAFKDYVAKWKD-NH2 616

Rev-R10-4F-2 Ac-FFERFAEAF RDYVAKWKD-NH2 617

Rev-R15-4F-2 Ac-FFEKFAEAFKDYVA RWKD-NH2 618

Rev-R17-4F-2 Ac-FFE RFAEAFKDYVAKW RD-NH2 619

Rev-[E3＞D]-4F-2 Ac-FF DKFAEAFKDYVAKWKD-NH2 620

Rev-[E7＞D]-4F-2 Ac-FFEKFA DAFKDYVAKWKD-NH2 621

Rev-[D11＞E]-4F-2 Ac-FFERFAEAFK EYVAKWKD-NH2 622

Rev-[D18＞E]-4F-2 Ac-FFERFAEAFKDYVAKWKE-NH2 623

Rev-7F Ac-FFEKFKEFFKDYFAKFWD-NH2 624

Rev-[E＞D]-7F Ac-FF DKFK DFFKDYFAKFWD-NH2 625

Rev-[D＞E]-7F Ac-FFEKFKEFFK EYFAKFW E-NH2 626

Rev-R4-7F Ac-FFE RFKEFFKDYFAKFWD-NH2 627

Rev-R6-7F Ac-FFEKF REFFKDYFAKFWD-NH2 628

Rev-R10-7F Ac-FFEKFKEFF RDYFAKFWD-NH2 629

Rev-R14-7F Ac-FFEKFKEFFKDYFA RFWD-NH2 630

Rev-[E3＞D]-7F Ac-FF DKFKEFFKDYFAKFWD-NH2 631

Rev-[E7＞D]7F Ac-FFEKFK DFFKDYFAKFWD-NH2 632

Rev-[D11＞E]-7F Ac-FFEKFKEFFK EYFAKFWD-NH2 633

Rev-[D18＞E]-7F Ac-FFEKFKEFFKDYFAKFW E-NH2 634

It is also noted that [0133] except meeting the corresponding natural amino acid that this paper identifies, any peptide as herein described can also comprise alpha-non-natural amino acid.This modification includes but not limited to acetylation, amidatioon, formylated, methylates, sulfation etc.Exemplary alpha-non-natural amino acid includes but not limited to ornithine, nor-leucine, norvaline, the N-methylvaline, the 6-N-methyllysine, N-methyl isoleucine, sarcosine, sarcosine, inosine, alloisoleucine, isodesmolysine, 4-Hydroxyproline, 3-Hydroxyproline, other hydroxylysine, hydroxylysine (hydoxylisine), the N-ethyl asparagine, Ethylglycocoll, 2, the 3-diaminopropionic acid, 2,2 '-diaminopropionic acid, desmosine, 2,4-diamino-butanoic, the 2-meso diaminopimelic acid, 3-diaminourea isopropylformic acid., 2-diaminourea isopropylformic acid., 2-diaminourea enanthic acid, 6-aminocaprolc acid, the 4-aminobutyric acid, the 2-aminobutyric acid, Beta-alanine, the 3-aminoadipic acid, 2-aminoadipic acid etc.In certain embodiments, any of peptide described herein or a plurality of " natural " aminoacid can be replaced by corresponding alpha-non-natural amino acid (for example above-mentioned aminoacid).

[0134] in certain embodiments, the present invention especially comprises the lysine that uses modification.This modification includes but not limited to the biotin modification of ε lysine and/or methylating of ε lysine.Comprising the methylate exemplary peptide of lysine of ε includes but not limited to: Ac-D-W-F-K (eCH ₃) ₂-A-F-Y-D-K (eCH ₃) ₂-V-A-E-K (eCH ₃) ₂-F-K (eCH ₃) ₂-E-A-F-NH (CH ₃) ₂(SEQ ID NO:635) and: Ac-DWFK (eCH ₃) ₂AFYDK (eCH ₃) ₂VAEK (eCH ₃) ₂FK (eCH ₃) ₂EAF-NH (CH ₃) (SEQID NO:636).The aminoacid of other modification includes but not limited to that ornithine analog and high amino alanine analog (homoaminoalanine analog) (replace (CH for Lys ₂) ₄-NH ₂, it can be-(CH for Haa ₂) ₂-NH ₂With it can be-(CH for Orn ₂) ₃-NH ₂] etc.

Be noted that these modifications are exemplary and not restrictive.Exemplary 4F analog with modified amino acid sees Table 6.

[0135] the 4F analog that comprises modified amino acid that table 6. is exemplary.

ε N-dimethyl-Lys derivant of 4F (ε N-Dime)
		Ac-D-W-F-K(εN-Dime)-A-F-Y-D-K(εN-Dime)-V-A-E-K(εN-Dime)-F-K(εN-Dime)-E-A-F-NH 2	637
Ac-D-W-F-K-(εN-Dime)-A-F-Y-D-K(εN-Dime)-V-A-E-K(εN-Dime)-F-K((εN-Dime)-E-A-F-NH-Me	638
		Ac-D-W-F-K-(εN-Dime)-A-F-Y-D-K(εN-Dime)-V-A-E-K(εN-Dime)-F-K(εN-Dime)-E-A-F-N-(Me) 2	639
ε N-diethyl-Lys derivant of 4F (ε N-Diet)
		Ac-D-W-F-K(εN-Diet)-A-F-Y-D-K(εN-Diet)-V-A-E-K(εN-Diet)-F-K(εN-Diet)-E-A-F-NH 2	640
Ac-D-W-F-K(εN-Diet)-A-F-Y-D-K(εN-Diet)-V-A-E-K(εN-Diet)-F-K(εN-Diet)-E-A-F-NH-Et	641
		Ac-D-W-F-K(εN-Diet)-A-F-Y-D-K(εN-Diet)-V-A-E-K(εN-Diet)-F-K(εN-Diet)-E-A-F-NH-(Et) 2	642
ε N-monomethyl-Lys derivant of 4F (ε N-Me)
		Ac-D-W-F-K(εN-Me)-A-F-Y-D-K(εN-Me)-V-A-E-K(εN-Me)-F-K(εN-Me)-E-A-F-NH 2	643
Ac-D-W-F-K(εN-Me)-A-F-Y-D-K(εN-Me)-V-A-E-K(εN-Me)-F-K(εN-Me)-E-A-F-NH-Me	644
		Ac-D-W-F-K(εN-Me)-A-F-Y-D-K(εN-Me)-V-A-E-K(εN-Me)-F-K(εN-Me)-E-A-F-N-(Me) 2	645
The ε N-ethyl Lys derivant of 4F (ε N-Et)
		Ac-D-W-F-K(εN-Et)-A-F-Y-D-K(εN-Et)-V-A-E-K(εN-Et)-F-K(εN-Et)-E-A-F-NH 2	646
Ac-D-W-F-K(εN-Et)-A-F-Y-D-K(εN-Et)-V-A-E-K(εN-Et)-F-K(εN-Et)-E-A-F-NH-Et	647
		Ac-D-W-F-K(εN-Et)-A-F-Y-D-K(εN-Et)-V-A-E-K(εN-Et)-F-K(εN-Et)-E-A-F-NH-(Et) 2	648

4F(hK)(-CH 2) 5-NH 2The HomoLys analog
		Ac-D-W-F-hK-A-F-Y-D-hK-V-A-E-hK-F-hK-E-A-F-NH 2	649
Ac-D-W-F-hK(εN-Dime)-A-F-Y-D-hK(εN-Dime)-V-A-E-hK(εN-Dime)-F-hK(εN-Dime)-E-A-F-NH 2	650
		Ac-D-W-F-hK(εN-Dime)-A-F-Y-D-hK(εN-Dime)-V-A-E-hK(εN-Dime)-F-hK(εN-Dime)-E-A-F-N-(Me) 2	651
Ac-D-W-F-hK(εN-Dime)-A-F-Y-D-hK(εN-Dime)-V-A-E-hK(εN-Dime)-F-hK(εN-Dime)-E-A-F-NH-Me	652
		Ac-D-W-F-hK(εN-Diet)-A-F-Y-D-hK(εN-Diet)-V-A-E-hK(εN-Diet)-F-hK(εN-Diet)-E-A-F-NH-Et	653
Ac-D-W-F-hK(εN-Me)-A-F-Y-D-hK(εN-Me)-V-A-E-hK(εN-Me)-F-hK(εN-Me)-E-A-F-NH 2	654
		Ac-D-W-F-hK(εN-Me)-A-F-Y-D-hK(εN-Me)-V-A-E-hK(εN-Me)-F-hK(εN-Me)-E-A-F-NH-Me	655
Ac-D-W-F-hK(εN-Me)-A-F-Y-D-hK(εN-Me)-V-A-E-hK(εN-Me)-F-hK(εN-Me)-E-A-F-N-(Me) 2	656
		Ac-D-W-F-hK(εN-Et)-A-F-Y-D-hK(εN-Et)-V-A-E-hK(εN-Et)-F-hK(εN-Et)-E-A-F-NH 2	657
Ac-D-W-F-hK(εN-Et)-A-F-Y-D-hK(εN-Et)-V-A-E-hK(εN-Et)-F-hK(εN-Et)-E-A-F-NH-Et	658
		Ac-D-W-F-hK(εN-Et)-A-F-Y-D-hK(εN-Et)-V-A-E-hK(εN-Et)-F-hK(εN-Et)-E-A-F-NH-(Et) 2	659
		K is by O (O=ornithine ,-(CH 2) 3-NH 2) metathetical 4F analog	660
Ac-D-W-F-O-A-F-Y-D-O-V-A-E-O-F-O-E-A-F-NH 2	661
		Ac-D-W-F-O(δN-Dime)-A-F-Y-D-O(δN-Dime)-V-A-E-O(δN-Dime)-F-O(δN-Dime)-E-A-F-NH 2	662
Ac-D-W-F-O(δN-Dime)-A-F-Y-D-)(δN-Dime)-V-A-E-O(δN-Dime)-F-O(δN-Dime)-E-A-F-N-(Me) 2	663
		Ac-D-W-F-O(δN-Dime)-A-F-Y-D-O(δN-Dime)-V-A-E-O(δN-Dime)-F-O(δN-Dime)-E-A-F-NH-Me	664
Ac-D-W-F-O(δN-Diet)-A-F-Y-D-O(δN-Diet)-V-A-E-O(δN-Diet)-F-O(δN-Diet)-E-A-F-NH-Et	665
		Ac-D-W-F-O(δN-Me)-A-F-Y-D-O(δN-Me)-V-A-E-O(δN-Me)-F-O(δN-Me)-E-A-F-NH 2	666
Ac-D-W-F-O(δN-Me)-A-F-Y-D-O(δN-Me)-V-A-E-O(δN-Me)-F-O(δN-Me)-E-A-F-NH-Me	667
		Ac-D-W-F-O(δN-Me)-A-F-Y-D-O(δN-Me)-V-A-E-O(δN-Me)-F-O(δN-Me)-E-A-F-N-(Me) 2	668
Ac-D-W-F-O(δN-Et)-A-F-Y-D-O(δN-Et)-V-A-E-O(δN-Et)-F-O(δN-Et)-E-A-F-NH 2	669
		Ac-D-W-F-O(δN-Et)-A-F-Y-D-O(δN-Et)-V-A-E-O(δN-Et)-F-O(δN-Et)-E-A-F-NH-Et	670
Ac-D-W-F-O(δN-Et)-A-F-Y-D-O(δN-Et)-V-A-E-OdεN-Et)-F-O(δN-Et)-E-A-F-NH-(Et) 2	671

Dime: dimethyl; Diet: diethyl; Me: methyl; Et: ethyl; HK: high-lysine; HomoLys: high-lysine

[0136] above-mentioned peptide and modified peptides are exemplary and not restrictive.

D) less peptide

[0137] finds also unexpectedly, by the one or more aminoacid of minimum 3 aminoacid (preferred (but be not essential) is amino acid whose D type stereoisomer) form and have the permission interactional hydrophobic domain of lipid protein and allow to a certain degree some little peptide of the hydrophilic domain of water-soluble, have significant antiinflammatory property equally, and can be used for treating one or more pathology described herein.The length range of " little peptide " is generally 2 aminoacid to about 15 aminoacid, and more preferably from about 3 aminoacid are to about 10 or 11 aminoacid, and most preferably from about 4 to about 8 or 10 aminoacid.In different embodiments, the feature of this peptide is to have on hydrophobic side aminoacid or the end amino acid usually has hydrophobicity by connecting one or more hydrophobic " protection " base.Various " little peptides " are on the books in following document: copending application USSN 10/649,378 (application on August 26th, 2003), USSN 10/913,800 and PCT application PCT/US2004/026288 (application on August 6th, 2004).

[0138] in certain embodiments, this peptide can characterize with following formula I:

X ¹-X ²-X ³ _n-X ⁴ I

Wherein, n is 0 or 1, X ¹For hydrophobic amino acid and/or have hydrophobic protecting group, X ⁴For hydrophobic amino acid and/or have hydrophobic protecting group; If n is 0, then X ²Be acidic amino acid or basic amino acid; If n is 1, then X ²And X ³Be acidic amino acid, basic amino acid, aliphatic amino acid or aromatic amino acid independently, if make X ²Be acidic amino acid, then X ³Be basic amino acid, aliphatic amino acid or aromatic amino acid; If X ²Be basic amino acid; X then ³Be acidic amino acid, aliphatic amino acid or aromatic amino acid; If X ²Be aliphatic amino acid or aromatic amino acid, then X ³Be acidic amino acid or basic amino acid.

[0139] long peptide (for example reaching 10,11 or 15 aminoacid) is also included within the scope of the present invention.Usually, feature at short peptide (for example peptide of formula I) is under the situation of acidic amino acid, basic amino acid, aliphatic amino acid or aromatic amino acid, and the feature of long peptide is to comprise the amino acid whose acidic domain of two or more same types, alkaline territory, aliphatic territory or aromatics territory.

1) functional character of active small peptide

[0140] the present invention finds unexpectedly, many physical propertys have indicated (for example 10 below the aminoacid of the little peptides of the present invention, preferred 8 below the aminoacid, more preferably from about 3 to about 5 or 6 aminoacid) following character: make HDL more antiinflammatory, alleviate the mammal atherosclerosis and/or be other pathology of feature with the inflammatory reaction.Physical property is included in dissolubility height in the ethyl acetate (for example＞about 4mg/ml) and dissolving in aqueous buffer solution (pH7.0).Under aqueous environments, with phospholipid for example 1, during two myristoyls of 2--sn-glyceryl-3-phosphocholine (DMPC) contact, effective especially little inducing peptide or participate in the about 7.5nm of diameter (± 0.1nm) particulate formation and/or induce or participate in double-deck size be about 3.4-4.1nm, buttress folded in the buttress of the about 2nm of spacing between the bilayer fold the formation of bilayer and/or also induce or participate in the formation of the vesicle structure of about 38nm.In certain preferred aspects, the molecular weight of little peptide＜about 900Da.

[0141] therefore, in certain embodiments, the present invention includes the little peptide of one or more symptoms of improving indication/pathology described herein (for example inflammatory diseases), this peptide wherein: length range about 3 to about 8 aminoacid, preferred about 3 to about 6 or 7 aminoacid, more preferably from about 3 to about 5 aminoacid; Concentration with＞about 4mg/ml is dissolved in ethyl acetate; Be dissolved in aqueous buffer solution during pH7.0; If in aqueous environments, contact, then form the granule of the about 7.5nm of diameter and/or form the folded bilayer of buttress that double-deck size is about the about 2nm of spacing between 3.4-4.1nm, the folded middle bilayer of buttress with phospholipid; Molecular weight＜about 900 dalton; Make short scorching HDL be transformed into antiinflammatory HDL or make antiinflammatory HDL antiinflammatory more; Do not have aminoacid sequence Lys-Arg-Asp-Ser (SEQ ID NO:801), especially Lys-Arg-Asp and Ser are L aminoacid.In certain embodiments, these little peptide protection phospholipid make its not oxidized dose of oxidation.

[0142] though these little peptides needn't be subjected to restriction like this, in certain embodiments, these little peptides can comprise following little peptide.

2) tripeptides

[0143] have now found that, can synthesize and have required character described herein (for example make short scorching HDL be transformed into the ability of antiinflammatory HDL, reduce by the active ability of the inductive monocyte chemotactic of the LDL that arterial wall cell produced, increase before the ability etc. of β HDL) tripeptides (3 amino acid whose peptides).In certain embodiments, this peptide characterizes with formula I, and wherein N is zero, then as shown in the formula shown in the II:

X ¹-X ²-X ⁴ II

Wherein, end amino acid (X ¹And X ⁴) because of hydrophobic side chain or because of side chain or C end and/or N end by one or more hydrophobic protecting groups sealings (for example N end with Boc-, Fmoc-, nicotinoyl (nicotinyl-) sealing of etc.ing, (the tBu)-sealings such as OtBu of C end), so be hydrophobic.In certain embodiments, X ²Aminoacid or be acid (for example aspartic acid, glutamic acid etc.) or be alkalescence (for example histidine, arginine, lysine etc.).This peptide can all be L-aminoacid or comprise one or more D-aminoacid that perhaps all are D-aminoacid.

[0144] some tripeptides of the present invention includes but not limited to peptide shown in the table 7.

[0145] table 7. some preferably have hydrophobic blocking groups and acidic amino acid, basic amino acid or histidine are the example of middle amino acid whose tripeptides.

X 1	X 2	X 3	X 4		SEQ ID NO
						Boc-Lys(εBoc) Boc-Lys(εBoc) Boc-Trp Boc-Trp Boc-Phe Boc-Phe Boc-Lys(εBoc) Boc-Lys(εBoc) Boc-Lys(εBoc) Boc-Lys(εBoc) Boc-Lys(εBoc) Boc-Lys(εBoc) Boc-Leu Boc-Leu Fmoc-Trp Fmoc-Trp Fmoc-Trp Fmoc-Trp Boc-Lys(εBoc) Fmoc-Leu Fmoc-Leu Fmoc-Leu Fmoc-Leu Fmoc-Leu Boc-Glu Fmoc-Lys(εFmoc) Fmoc-Trp Fmoc-Trp Fmoc-Phe	Arg Arg Arg Arg Arg Arg Glu Glu Asp Asp Arg Arg Glu Glu Arg Asp Glu Arg Glu Arg Asp Glu Arg Arg Asp Arg Arg Arg Arg		Ser(tBu)-OtBuThr(tBu)-OtBuIle-OtBuLeu-OtBuIle-OtBuLeu-OtBuSer(tBu)-OtBuThr(tBu)-OtBuSer(tBu)-OtBuThr(tBu)-OtBuSer(tBu)-OtBuThr(tBu)-OtBuSer(tBu)-OtBuThr(tBu)-OtBuSer(tBu)-OtBuSer(tBu)-OtBuSer(tBu)-OtBuSer(tBu)-OtBuLeu-OtBuSer(tBu)-OtBuSer(tBu)-OtBuSer(tBu)-OtBuSer(tBu)-OtBuThr(tBu)-OtBuTyr(tBu)-OtBuSer(tBu)-OtBuIle-OtBuLeu-OtBuIle-OtBu		672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700

Fmoc-Phe Boc-Trp Boc-Trp Fmoc-Trp Fmoc-Trp Boc-Orn(δBoc) Nicotinyl Lys(εBoc) Nicotinyl Lys(εBoc) Fmoc-Leu Fmoc-Leu Fmoc-Leu Fmoc-norLeu Fmoc-norLeu Fmoc-norLeu Fmoc-Lys(εBoc) Fmoc-Lys(εBoc) Fmoc-Lys(εB oc) Fmoc-Lys(εBoc) Fmoc-Lys(εBoc) Fmoc-Lys(εBoc) Fmoc-Lys(εBoc) Fmoc-Lys(εBoc) Fmoc-Lys(εFmoc) Fmoc-Lys(εFmoc) Fmoc-Lys(εFmoc) Fmoc-Lys(εFmoc) Fmoc-Lys(εFmoc) Fmoc-Lys(εFmoc) Fmoc-Lys(εFmoc)) Boc-Lys(εFmoc) Boc-Lys(εFmoc) Boc-Lys(εFmoc) Boc-Lys(εFmoc) Boc-Orn(δFmoc) Boc-Orn(δFmoc) Boc-Orn(δFmoc) Boc-Orn(δFmoc) Boc-Orn(δFmoc) Fmoc-Trp Fmoc-Trp Fmoc-Trp Fmoc-Trp

Arg Arg Arg Arg Arg Arg Arg Arg Asp Glu Arg Arg Asp Glu Arg Arg Glu Glu Asp Asp Glu Arg Arg Glu Glu Asp Asp Arg Glu Asp Asp Arg Glu Glu Asp Asp Arg Glu Asp Arg Glu Asp

Leu-OtBu Phe-OtBu Tyr-OtBu Phe-OtBu Tyr-OtBu Ser(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Thr(tBu)-OtBu Thr(tBu)-OtBu Thr(tBu)-OtBu Ser(tBu)-OtBu Ser(tBu)-OtBu Ser(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Leu-OtBu Leu-OtBu Thr(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Ser(tBu)-OtBu Leu-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Thr(tBu)-OtBu Leu-OtBu Ser(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Thr(tBu)-OtBu Thr(tBu)-OtBu Ile-OtBu Ile-OtBu Ile-OtBu Leu-OtBu

701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742

Fmoc-Trp Fmoc-Phe Fmoc-phe Fmoc-Phe Fmoc-Trp Fmoc-Irp Fmoc-Trp Fmoc-Trp Fmoc-Trp Fmoc-Trp Fmoc-Trp Fmoc-Trp Fmoc-Trp Boc-Phe Boc-Phe Fmoc-Phe Boc-Glu Boc-Leu Boc-Leu Boc-Lys(εBoc) Boc-Lys(εBoc) Boc-Lys(εBoc) Boc-Lys(εFmoc) Boc-Lys(εFmoc) Boc-Lys(εFmoc) Boc-Om(δBoc) Boc-Om(δFmoc) Boc-Phe Boc-Phe Boc-Phe Boc-Phe Boc-Trp Boc-Trp Boc-Trp Boc-Trp Boc-Phe Fmoc-Lys(εFmoc)

Glu Asp Asp Glu Arg Glu Asp Asp Arg Glu Arg Asp Glu Arg Glu Asp His His His His His His His His His His His His His His Lys His His His His Lys His

Leu-OtBu Ile-OtBu Leu-OtBu Leu-OtBu Phe-OtBu Phe-OtBu Phe-OtBu Tyr-OtBu Tyr-OtBu Tyr-OtBu Thr(tBu)-OtBu Thr(tBu)-OtBu Thr(tBu)-OtBu norLeu-OtBu norLeu-OtBu norLeu-OtBu Tyr(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Leu-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Leu-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Ile-OtBu Leu-OtBu norLeu-OtBu Leu-OtBu Ile-OtBu Leu-OtBu Phe-OtBu Tyr-OtBu Leu-OtBu Ser(tBu)-OtBu

743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 776 777 778 779

Fmoc-Lys(εFmoc) Fmoc-Lys(εFmoc) Fmoc-Leu Fmoc-Leu Fmoc-Lys(εBoc) Fmoc-Lys(εBoc) Fmoc-Lys(εBoc) Fmoc-Lys(εFmoc) Fmoc-Lys(εFmoc) Fmoc-norLeu Fmoc-Phe Fmoc-Phe Fmoc-Phe Fmoc-Trp Fmoc-Trp Fmoc-Trp Fmoc-Trp Fmoc-Trp Fmoc-Trp Nicotinyl Lys(εBoc) Nicotinyl Lys(εBoc)

His His His His His His His His His His His His His His His His His His His His His

Thr(tBu)-OtBu Leu-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Leu-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Ser(tBu)-OtBu IIe-OtBu Leu-OtBu norLeu-OtBu Ser(tBu)-OtBu Ile-OtBu Leu-OtBu Phe-OtBu Tyr-OtBu Thr(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu

780 781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800

[0146] though table 7 expression be peptide with special protection base, be noted that these groups can be with other protecting group replacement as herein described, and/or can slough one or more shown in protecting group.

3) has the little peptide of middle acidic amino acid and basic amino acid

[0147] in certain embodiments, the scope of peptide of the present invention is that 4 aminoacid are to about 10 aminoacid.End amino acid or because of hydrophobic side chain or because of end amino acid has one or more more hydrophobic protecting groups, so normally hydrophobic.End amino acid (X ¹And X ⁴) because of hydrophobic side chain or because of side chain or C end and/or N end by one or more hydrophobic protecting groups sealings (for example N end by Boc-, Fmoc-, nicotinoyl (Nicotinyl-) sealing of etc.ing, (the tBu)-sealings such as OtBu of C end quilt), so be hydrophobic.Usually, the peptide of mid portion comprises basic amino acid and acidic amino acid (for example in the tetramer) or alkaline territory and/or acidic domain in longer molecule.

[0148] these tetramers can be represented with formula I, wherein X ¹And X ⁴Be hydrophobic and/or have hydrophobic protecting group as herein described, if X ³Be alkaline, X then ²Be tart, perhaps work as X ³Be tart, X then ²Be alkaline.This peptide can all be L-aminoacid or comprise one or more D-aminoacid that perhaps all are D-aminoacid.

[0149] some preferred peptide of the present invention includes but not limited to peptide shown in the table 8.

[0150] table 8. has the illustrative examples of the little peptide of middle acidic amino acid and basic amino acid.

X 1	X 2	X 3	X 4	SEQ ID NO
					Boc-Lys(εBoc) Boc-Lys(εBoc) Boc-Trp Boc-Trp Boc-Phe Boc-Phe Boc-Phe Boc-Phe Boc-Phe Boc-Phe Boc-Phe Boc-Phe Boc-Phe Boc-Phe Boc-Phe Boc-Phe Boc-Lys(εBoc) Boc-Lys(εBoc) Boc-Lys(εBoc) Boc-Lys(εBoc) Boc-Lys(εBoc) Boc-Lys(εBoc) Boc-Leu	Arg Arg Arg Arg Arg Arg Arg Arg Arg Asp Glu Asp Arg Glu Asp Glu Glu Glu Asp Asp Arg Arg Glu	Asp Asp Asp Asp Asp Asp Asp Glu Glu Arg Arg Arg Glu Arg Arg Arg Arg Arg Arg Arg Glu Glu Arg	Ser(tBu)-OtBu Thr(tBu)-OtBu Ile-OtBu Leu-OtBu Leu-OtBu Ile-OtBu norLeu-OtBu norLeu-OtBu Ile-OtBu Ile-OtBu Ile-OtBu Leu-OtBu Leu-OtBu Leu-OtBu norLeu-OtBu norLeu-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Ser(tBu)-OtBu	801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823

Boc-Leu Fmoc-Trp Fmoc-Trp Fmoc-Trp Fmoc-Trp Boc-Lys(εBoc) Fmoc-Leu Fmoc-Leu Fmoc-Leu Fmoc-Leu Fmoc-Leu Boc-Glu Fmoc-Lys(εFmoc) Fmoc-Trp Fmoc-Trp Fmoc-Phe Fmoc-Phe Boc-Trp Boc-Trp Fmoc-Trp Fmoc-Trp Boc-Orn(δBoc) Nicotinyl Lys(εBoc) Nicotinyl Lys(εBoc) Fmoc-Leu Fmoc-Leu Fmoc-Leu Fmoc-norLeu Fmoc-norLeu Fmoc-norLeu Fmoc-norLeu Fmoc-Lys(εBoc) Fmoc-Lys(εBoc) Fmoc-Lys(εBoc) Fmoc-Lys(εBoc) Fmoc-Lys(εBoc) Fmoc-Lys(εBoc) Fmoc-Lys(εBoc) Fmoc-Lys(εBoc) Fmoc-Lys(εBoc)

Glu Arg Asp Glu Arg Glu Arg Asp Glu Arg Arg Asp Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Asp Glu Arg Arg Asp Glu Arg Arg Arg Glu Glu Asp Asp Arg Arg Glu

ArgAspArgArgGluArgAspArgArgGluAspArgAspAspAspAspAspAspAspAspAspGluAspAspArgArgGluAspArgArgGluAspAspArgArgArgArgGluGluArg

Thr(tBu)-OtBu Ser(tBu)-OtBu Ser(tBu)-OtBu Ser(tBu)-OtBu Ser(tBu)-OtBu Leu-OtBu Ser(tBu)-OtBu Ser(tBu)-OtBu Ser(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Tyr(tBu)-OtBu Ser(tBu)-OtBu Ile-OtBu Leu-OtBu Ile-OtBu Leu-OtBu Phe-OtBu Tyr-OtBu Phe-OtBu Tyr-OtBu Ser(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Thr(tBu)-OtBu Thr(tBu)-OtBu Thr(tBu)-OtBu Ser(tBu)-OtBu Ser(tBu)-OtBu Ser(tBu)-OtBu Ser(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Leu-OtBu

824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863

Fmoc-Lys(εBoc) Fmoc-Lys(εFmoc) Fmoc-Lys(εFmoc) Fmoc-Lys(εFmoc) Fmoc-Lys(εFmoc) Fmoc-Lys(εFmoc) Fmoc-Lys(εFmoc) Fmoc-Lys(εFmoc) Fmoc-Lys(εFmoc)) Boc-Lys(εFmoc) Boc-Lys(εFmoc) Boc-Lys(εFmoc) Boc-Lys(εFmoc) Boc-Lys(εFmoc) Boc-Lys(εFmoc) Boc-Lys(εFmoc) Boc-Lys(εFmoc) Boc-Lys(εFmoc) Boc-Orn(δFmoc) Boc-Orn(δFmoc) Boc-Orn(δFmoc) Boc-Orn(δFmoc) Boc-Orn(δFmoc) Boc-Orn(δFmoc) Boc-Orn(δFmoc) Boc-Orn(δFmoc) Fmoc-Trp Fmoc-Trp Fmoc-Trp Fmoc-Trp Fmoc-Trp Fmoc-Trp Fmoc-Phe Fmoc-Phe Fmoc-Phe Fmoc-Phe Fmoc-Phe Fmoc-Phe Fmoc-Trp Fmoc-Trp

Arg Arg Glu Glu Asp Asp Arg Arg Glu Arg Arg Glu Glu Asp Asp Arg Arg Glu Arg Glu Arg Asp Asp Arg Glu Arg Asp Arg Glu Asp Arg Glu Asp Arg Glu Asp Arg Glu Arg Arg

GluAspArgArgArgArgGluGluArgAspAspArgArgArgArgGluGluArgGluArgAspArgArgAspArgGluArgGluArgArgGluArgAarGluArgArgGluArgAspGlu

Leu-OtBu Thr(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Leu-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Leu-OtBu Ser(tBu)-OtBu Ser(tBu)-OtBu Ser(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Thr(tBu)-OtBu Thr(tBu)-OtBu Thr(tBu)-OtBu Ile-OtBu Ile-OtBu Ile-OtBu Leu-OtBu Leu-OtBu Leu-OtBu Ile-OtBu Ile-OtBu Ile-OtBu Leu-OtBu Leu-OtBu Leu-OtBu Phe-OtBu Phe-OtBu

864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885 886 887 888 889 890 891 892 893 894 895 896 897 898 899 900 901 902 903

Fmoc-trp Fmoc-Trp Fmoc-Trp Fmoc-Trp Fmoc-Trp Fmoc-Trp Fmoc-Trp Fmoc-Trp Fmoc-Phe Fmoc-Phe Boc-Phe Boc-Phe Boc-Phe Boc-Phe Boc-Phe Boc-Phe Boc-Phe Boc-Phe Boc-Phe Boc-Phe Boc-Phe Boc-Phe Boc-Phe Boc-Phe Boc-Phe Boc-Phe Boc-Phe Boc-Phe Boc-Phe Boc-Phe Boc-Phe Boc-Phe Boc-Phe Boc-Phe Boc-Lys(εBoc) Boc-Lys(εBoc) Boc-Lys(εBoc) Boc-Lys(εBoc) Boc-Lys(εBoc) Boc-Lys(εBoc) Boc-Lys(εBoc)

Glu Asp Arg Glu Arg Asp Arg Glu Arg Arg Lys Asp Lys Glu Lys Asp Lys Glu Lys Asp Lys Glu His Asp His Glu His Asp His Glu His Asp His Glu Lys Asp Lys Glu His Asp His

Arg Arg Glu Arg Asp Arg Glu Arg Asp Glu Asp Lys Glu Lys Asp Lys Glu Lys Asp Lys Glu Lys Asp His Glu His Asp His Glu His Asp His Glu His Asp Lys Glu Lys Asp His Glu

Phe-OtBu Tyr-OtBu Tyr-OtBu Tyr-OtBu Thr(tBu)-OtBu Thr(tBu)-OtBu Thr(tBu)-OtBu Thr(tBu)-OtBu norLeu-OtBu norLeu-OtBu Leu-OtBu Leu-OtBu Leu-OtBu Leu-OtBu Ile-OtBu Ile-OtBu Ile-OtBu Ile-OtBu norLeu-OtBu norLeu-OtBu norLeu-OtBu norLeu-OtBu Leu-OtBu Leu-OtBu Leu-OtBu Leu-OtBu Ile-OtBu Ile-OtBu Ile-OtBu Ile-OtBu norLeu-OtBu norLeu-OtBu norLeu-OtBu norLeu-OtBu Ser(tBu)-OtBu Ser(tBu)-OtBu Ser(tBu)-OtBu Ser(tBu)-OtBu Ser(tBu)-OtBu Ser(tBu)-OtBu Ser(tBu)-OtBu

904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944

Boc-Lys(εBoc)

Glu

His

Ser(tBu)-OtBu

945

[0151] though table 8 expression be peptide with special protection base, be noted that these groups can be with other protecting group replacement as herein described, and/or can slough one or more shown in protecting group.

4) have acidic amino acid or basic amino acid and middle aliphatic amino acid in the middle of Little peptide

[0152] in certain embodiments, the scope of peptide of the present invention is that 4 aminoacid are to about 10 aminoacid.End amino acid is because of hydrophobic side chain or because of end amino acid has one or more hydrophobic protecting groups, so normally hydrophobic.End amino acid (X ¹And X ⁴) because of hydrophobic side chain or because of side chain or C end and/or N end by one or more hydrophobic protecting groups sealings (for example N end by Boc-, Fmoc-, nicotinoyl (Nicotinyl-) sealing of etc.ing, (the tBu)-sealings such as OtBu of C end quilt), so be hydrophobic.Usually, the peptide of mid portion comprises basic amino acid or acidic amino acid and aliphatic amino acid (for example in the tetramer) or the alkaline territory in longer molecule or acidic domain and aliphatic territory.

[0153] these tetramers can be represented by formula I, wherein X ¹And X ⁴Be hydrophobic and/or have hydrophobic protecting group as herein described, if X ³Be aliphatic, X then ²Be acid or alkaline, if perhaps X ³Be acidity or alkaline, then X ²Be aliphatic.This peptide can all be L-aminoacid or comprise one or more D-aminoacid that perhaps all are D-aminoacid.

[0154] some preferred peptide of the present invention includes but not limited to the listed peptide of table 9.

[0155] some preferred middle example of table 9. with peptide of acidic amino acid or basic amino acid and middle aliphatic amino acid.

X 1	X 2	X 3	X 4	SEQ ID NO
					Fmoc-Lys(εBoc)Fmoc-Lys(εBoc)Fmoc-Lys(εBoc)Fmoc-Lys(εBoc)Fmoc-Lys(εBoc)Fmoc-Lys(εBoc)Fmoc-Lys(εBoc)Fmoc-Lys(εBoc)Fmoc-Lys(εFmoc)Fmoc-Lys(εFmoc)Fmoc-Lys(εFmoc)Fmoc-Lys(εFmoc)Boc-Lys(Fmoc)Boc-Lys(εFmoc)Boc-Lys(εFmoc)Boc-Lys(εFmoc)Boc-Lys(εFmoc)Boc-Lys(εBoc)Boc-Lys(εBoc)Boc-Lys(εBoc)Boc-Lys(εBoc)Boc-Lys(εBoc)Boc-Lys(εBoc)Boc-Lys(εBoc)Boc-Lys(εBoc)Boc-Lys(εBoc)	Leu Arg Leu Arg Glu Leu Glu Leu Leu Leu Glu Glu Glu Leu Leu Glu Glu Leu Arg Leu Glu Glu Glu Glu Glu Glu	Arg Leu Arg Leu Leu Glu Leu Glu Arg Arg Leu Leu Ile Arg Arg Leu Leu Arg Phe Arg Ile Val Ala Gly Leu Leu	Ser(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Thr(tBu)-OtBu Ser(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Thr(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Thr(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Ser(tBu)-OtBu Thr(tBu)-OtBu Thr(tBu)-OtBu Thr(tBu) Thr(tBu) Thr(tBu) Thr(tBu) Ser(tBu)-OtBu Thr(tBu)-OtBu	946 947 948 949 950 951 952 953 954 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969 970 971

[0156] though table 9 expression be peptide with special protection base, be noted that these groups can be with other protecting group replacement as herein described, and/or can slough one or more shown in protecting group.

5) centre has acidic amino acid or basic amino acid and middle aromatic amino acid Little peptide

[0157] in certain embodiments, " little " of the present invention peptide scope is that 4 aminoacid are to about 10 aminoacid.End amino acid is because of hydrophobic side chain or because of end amino acid has one or more hydrophobic protecting groups, so normally hydrophobic.End amino acid (X ¹And X ⁴) because of hydrophobic side chain or because of side chain or C end and/or N end by one or more hydrophobic protecting groups sealings (for example N end by Boc-, Fmoc-, nicotinoyl (Nicotinyl-) sealing of etc.ing, (the tBu)-sealings such as OtBu of C end quilt), so be hydrophobic.Usually, the peptide of mid portion comprises basic amino acid or acidic amino acid and aromatic amino acid (for example in the tetramer) or the alkaline territory in longer molecule or acidic domain and aromatics territory.

[0158] these tetramers can be represented with formula I, wherein X ¹And X ⁴Be hydrophobic and/or have hydrophobic protecting group as herein described, if X ³Be aromatics, X then ²Be acid or alkaline, if perhaps X ³Be acidity or alkaline, then X ²Be aromatics.This peptide can all be L-aminoacid or comprise one or more D-aminoacid that perhaps all are D-aminoacid.Pentamer can be modified with the minimum of formula I and represent, wherein inserts X ⁵, see Table 10, wherein X ⁵Be generally aromatic amino acid.

[0159] some preferred peptide of the present invention includes but not limited to peptide shown in the peptide table 10.

[0160] some preferred middle example of table 10. with peptide of acidic amino acid or basic amino acid and middle aromatic amino acid.

X 1	X 2	X 3	X 5	X 4	SEQ ID NO
						Fmoc-Lys(εBoc)Fmoc-Lys(εBoc)Fmoc-Lys(εBoc)Fmoc-Lys(εBoc)Fmoc-Lys(εBoc)Fmoc-Lys(εBoc)Fmoc-Lys(εBoc)Fmoc-Lys(εFmoc)Fmoc-Lys(εFmoc)Fmoc-Lys(εFmoc)Fmoc-Lys(εFmoc)Fmoc-Lys(εFmoc)Boc-Lys(εFmoc)Boc-Lys(εFmoc)Boc-Lys(εFmoc)Boc-Lys(εFmoc)Boc-Lys(εFmoc)Boc-GluBoc-Lys(εBoc)Boc-Lys(εBoc)Boc-Lys(εBoc)Boc-Lys(εBoc)Boc-Lys(εBoc)Boc-Lys(εBoc)	Arg Trp Arg Tyr Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Arg Lys(εFmoc) Arg Arg Arg Arg Arg Arg	Trp Arg Tyr Arg Tyr Tyr Trp Trp Tyr Tyr Tyr Trp Trp Tyr Tyr Tyr Trp Arg Trp Tyr Tyr Tyr Phe Trp	Trp Trp Trp Trp	Tyr(tBu)-OtBu Tyr(tBu)-OtBu Trp-OtBu Trp-OtBu Thr(tBu)-OtBu Thr(tBu)-OtBu Thr(tBu)-OtBu Tyr(tBu)-OtBu Trp-OtBu Thr(tBu)-OtBu Thr(tBu)-OtBu Thr(tBu)-OtBu Tyr(tBu)-OtBu Trp-OtBu Thr(tBu)-OtBu Thr(tBu)-OtBu Thr(tBu)-OtBu Tyr(tBu)-OtBu Tyr(tBu)-OtBu Trp-OtBu Thr(tBu)-OtBu Thr(tBu)-OtBu Thr(tBu)-OtBu Thr(tBu)-OtBu	972 973 974 975 976 977 978 979 980 981 982 983 984 985 986 987 988 989 990 991 992 993 994 995

[0161] though table 10 expression be peptide with special protection base, be noted that these groups can be with other protecting group replacement as herein described, and/or can slough one or more shown in protecting group.

6) have aromatic amino acid or little by the separated aromatic amino acid of histidine in the middle of Peptide

[0162] in certain embodiments, the feature of peptide of the present invention is to be exposed to the intermediary pi-electron of molecule, this allows the granule hydration, and then the permission peptide particles is caught the phospholipid of urging scorching lipid oxide (for example fatty acid hydroperoxide) and containing the arachidonic acid oxidation product in the sn-2 position.

[0163] in certain embodiments; these peptides are made up of minimum 4 aminoacid and maximum about 10 aminoacid; preferably (but be not must) one or more aminoacid are amino acid whose D-isomer; (for example the N end is by Boc-, Fmoc-, nicotinoyl sealings such as (Nicotinyl-) because of hydrophobic side chain or because of end amino acid has one or more hydrophobic blocking groupses for end amino acid; the C end is by sealings such as (tBu)-OtBu groups), so be hydrophobic.These peptides have aromatic amino acid usually or have by the separated aromatic amino acid of histidine in the centre of peptide in the centre, rather than the centre has acidic amino acid or basic amino acid.

[0164] some preferred peptide of the present invention includes but not limited to peptide shown in the table 11.

[0165] has aromatic amino acid in the middle of the table 11. or by the example of the peptide in separated aromatic amino acid of one or more histidine or aromatics territory.

X 1	X 2	X 3	X 4	X 5	SEQ ID NO
						Boc-Lys(εBoc)Boc-Lys(εBoc)Boc-Lys(εBoc)Boc-Lys(εBoc)Boc-Lys(εBoc)Boc-Lys(εBoc)Boc-Lys(εBoc)Nicotinyl-Lys(εBoc)Nicotinyl-Lys(εBoc)Nicotinyl-Lys(εBoc)Nicotinyl-Lys(εBoc)Nicotinyl-Lys(εBoc)Nicotinyl-Lys(εBoc)Boc-LeuBoc-Leu	Phe Phe Phe Phe Phe Phe Val Phe Phe Phe Phe Phe Phe Phe Phe	Trp Trp Tyr Tyr His His Phe Trp Trp Tyr Tyr His His Trp Trp	Phe Phe Phe Phe Phe Phe Phe-Tyr Phe Phe Phe Phe Phe Phe Phe Phe	Ser(tBu)-OtBuThr(tBu)-OtBuSer(tBu)-OtBuThr(tBu)-OtBuSer(tBu)-OtBuThr(tBu)-OtBuSer(tBu)-OtBuSer(tBu)-OtBuThr(tBu)-OtBuSer(tBu)-OtBuThr(tBu)-OtBuSer(tBu)-OtBuThr(tBu)-OtBuThr(tBu)-OtBuSer(tBu)-OtBu	996 997 998 999 1000 1001 1002 1003 1004 1005 1006 1007 1008 1009 1010

[0166] though table 11 expression be peptide with special protection base, be noted that these groups can be with other protecting group replacement as herein described, and/or can slough one or more shown in protecting group.

7) tripeptides and tetrapeptide general introduction

[0167] for clarity sake, many tripeptides of the present invention and tetrapeptide are summarized in table 12.

[0168] basic structure of some peptide of table 12. the present invention.

X 1	X 2	X 3	X 4
				Hydrophobic side chain or hydrophobic protecting group hydrophobic side chain or hydrophobic protecting group hydrophobic side chain or hydrophobic protecting group hydrophobic side chain or hydrophobic protecting group hydrophobic side chain or hydrophobic protecting group hydrophobic side chain or hydrophobic protecting group hydrophobic side chain or hydrophobic protecting group hydrophobic side chain or hydrophobic protecting group	Acid or the alkaline aromatics aromatics of acid or alkaline acidic acid or alkaline fat family	Acid or the alkaline His aromatics of----acid alkaline aliphatic acid or alkaline aromatics	Hydrophobic side chain or hydrophobic protecting group hydrophobic side chain or hydrophobic protecting group hydrophobic side chain or hydrophobic protecting group hydrophobic side chain or hydrophobic protecting group hydrophobic side chain or hydrophobic protecting group hydrophobic side chain or hydrophobic protecting group hydrophobic side chain or hydrophobic protecting group hydrophobic side chain or hydrophobic protecting group

[0169] when the long peptide of needs, X ²And X ³But representative domain (for example two or more aminoacid district of specific type) rather than single amino acids.Table 12 is exemplary and not restrictive.Use the instruction that this paper provided, can easily identify other suitable peptide.

8) matching amino acid and dipeptides

[0170] in certain embodiments, the present invention relates to some paired aminoacid can combine with one another and give or be connected to form the dipeptides with one or more character described herein.Therefore, be not subjected under the situation of particular theory constraint, we think and combine with one another when giving when paired aminoacid as herein described that they can participate in or induce micellar formation in vivo.

[0171] is similar to other little peptide as herein described, it is believed that paired peptide will associate in vivo, and show dissolved physical property in the dissolubility height comprise in the ethyl acetate (for example＞about 4mg/ml), the aqueous buffer solution (pH7.0).Under aqueous environments, with phospholipid for example 1, during two myristoyls of 2--sn-glyceryl-3-phosphocholine (DMPC) contact, it is believed that paired aminoacid induce or participate in forming the about 7.5nm of diameter (± 0.1nm) granule and/or induce or participate in forming the about 3.4-4.1nm of double-deck size, buttress folded in the buttress of the about 2nm of spacing between the bilayer fold bilayer and/or also induce or participate in forming the vesicle structure of about 38nm.

[0172] in addition, we think that also paired aminoacid can have following one or more physiologys and go up relevant character:

[0173] 1. make short scorching HDL be transformed into antiinflammatory HDL or make antiinflammatory HDL antiinflammatory more;

[0174] 2. reduces by the inductive monocyte chemotactic activity of the LDL that arterial wall cell produced;

[0175] 3. formation and the circulation of the preceding β HDL of stimulation;

[0176] 4. improves the HDL cholesterol; And/or

[0177] 5. strengthens HDL paraoxonase activity.

[0178] in pairs aminoacid can be used as independent aminoacid and gives (can give sequential or simultaneously, for example give to mix dosage form), perhaps directly covalent coupling or by joint (for example PEG joint, carbon atom joint, prop up chain joint, straight chain joint, heterocycle joint, the formed joint of derivatization lipid etc.).In certain embodiments, aminoacid passes through the covalently bound formation dipeptides of peptide bond in pairs.In different embodiments, dipeptides comprises 2 aminoacid that respectively have the supplementary protection base usually, and the present invention only comprises also wherein that an aminoacid has the dipeptides of one or more protecting groups.

[0179] in pairs aminoacid comprises the aminoacid that each aminoacid wherein is connected with at least one protecting group (hydrophobic protecting group for example described herein) usually.Aminoacid can be D type or L type.In certain embodiments, comprise paired aminoacid and do not connect to each other, each aminoacid has 2 protecting groups (for example molecule 1 in the table 13 and molecule 2).

[0180] the exemplary aminoacid of table 13. the present invention is right.

Aminoacid is right/dipeptides
	1.Boc-Arg-OtBu *2.Boc-Glu-OtBu *3.Boc-Phe-Arg-OtBu **4.Boc-Glu-Leu-OtBu **5.Boc-Arg-Glu-OtBu ***

^*Usually can unite with second aminoacid and give.

^*In certain embodiments, these dipeptides can combine with one another and give.

^{* *}In certain embodiments, this peptide can give separately or unite with a kind of other peptide as herein described to give.

[0181] by provide shielded aminoacid to and/or shielded dipeptides, then the screening have the aminoacid of one or more above-mentioned physical propertys and/or physiological characteristics right/dipeptides, can easily identify suitable paired aminoacid.In certain embodiments, the present invention do not comprise the aminoacid that contains aspartic acid and phenylalanine to and/or dipeptides.In certain embodiments, the present invention does not comprise that one of them aminoacid is (-)-N-[(trans-4-isopropyl cyclohexane extraction) carbonyl]-aminoacid of D-phenylalanine (Nateglinide) to and/or dipeptides.

[0182] in certain embodiments, comprise paired aminoacid and independently be selected from following aminoacid: acidic amino acid (for example aspartic acid, glutamic acid etc.), basic amino acid (for example lysine, arginine, histidine etc.) and nonpolar amino acid (for example alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine etc.).In certain embodiments, when first aminoacid is acid or alkaline, then second aminoacid is nonpolar, and when second aminoacid is acid or alkaline, then first aminoacid is nonpolar.In certain embodiments, when first aminoacid is tart, then second aminoacid is alkaline, and vice versa.(referring to for example table 14).

[0183] can obtain similar combination by giving paired dipeptides.Therefore for example in certain embodiments, molecule 3 in the table 13 and molecule 4 can combine with one another and give.

Some common aminoacid of table 14. is right/dipeptides.

	First aminoacid	Second aminoacid
			1. 2. 3. 4. 5. 6.	The acid nonpolar alkalescence of acid alkalescence is nonpolar	The nonpolar alkalescence of the acid nonpolar acidity of alkalescence

[0184] be noted that these aminoacid right/dipeptides is exemplary and not restrictive.Use the instruction that this paper provided, can easily determine other suitable aminoacid right/dipeptides.

E) Apo-J (G ^*Peptide)

[0185] the present invention finds, the peptide in simulation apo J amphipathic helix territory can alleviate one or more symptoms of atherosclerosis and/or other pathology as herein described.Apolipoprotein J has the globular protein of being called as sample territory or G ^*The roomy non-polar plane in amphipathic helix territory.G class amphipathic helix is present in the globular protein, so called after G class.The feature of this class amphipathic helix is that positively charged residue and electronegative residue are randomly dispersed on the polar surface of narrow non-polar plane.Because narrow non-polar plane, this class are difficult for associating with phospholipid.G ^*The class amphipathic helix has the feature similar but inequality to the G amphipathic helix.Similar with G class amphipathic helix, G ^*The class peptide has the positively charged residue of random distribution and electronegative residue on polar surface.Yet opposite with the G class amphipathic helix with narrow non-polar plane, this class has roomy non-polar plane, allows such easy and phospholipids incorporate, and such is named as G ^*The class amphipathic helix is to be different from G class amphipathic helix.

[0186] many suitable G ^*Amphipathic peptide is on the books in following document: copending application USSN10/120,508 (applications on April 5th, 2002), USSN10/520,207 (applications on April 1st, 2003) and PCT application PCT/US03/09988 (application on April 1st, 2003).In addition, the present invention is many and the G of apo J ^*The appropriate peptide that the amphipathic helix territory is relevant sees Table 15.

[0187] table 15. some be used for the present invention and apo J G ^*The peptide that the amphipathic helix territory is relevant.

Aminoacid sequence	SEQ ID NO
		LLEQLNEQFNWVSRLANLTQGE LLEQLNEQFNWVSRLANL NELQEMSNQGSKYVNKEIQNAVNGV IQNAVNGVKQIKTLIEKTNEE RKTLLSNLEEAKKKKEDALNETRESETKLKEL PGVCNETMMALWEECK PCLKQTCMKFYARVCR ECKPCLKQTCMKFYARVCR LVGRQLEEFL MNGDRIDSLLEN QQTHMLDVMQD FSRASSIIDELFQD PFLEMIHEAQQAMDI PTEFIREGDDD RMKDQCDKCREILSV PSQAKLRRELDESLQVAERLTRKYNELLKSYQ LLEQLNEQFNWVSRLANLTEGE DQYYLRVTTVA PSGVTEVVVKLFDS PKEMETVAEKALQEYRKKHRE	1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030

[0188] yet, peptide of the present invention is not limited to the G of apo J ^*Variant.Generally speaking, derive from any other protein, the preferred proteic G of apo basically ^*The territory also suits.Use protection active (for example protect LDL make it not oxidized etc.) algoscopy, for example method described in this paper embodiment can easily be determined these protein that suit especially.Some particularly preferred protein comprise proteinic G ^*Amphipathic helix territory or its variant (for example guarding replacement etc.) include but not limited to apo AI, apo AIV, apo E, apo CII, apo CIII etc.

[0189] some preferably with apoprotein rather than the relevant G of apo J ^*Amphipathic helix territory related peptides sees Table 16.

[0190] table 16. some be used for of the present invention and apoprotein rather than the relevant G of apo J ^*Amphipathic helix territory related peptides.

Aminoacid sequence	SEQ ID NO
		WDRVKDLATVYVDVLKDSGRDYVSQF (relevant with the 8-33 district of apo AI) VATVMWDYFSQLSNNAKEAVEHLQK (relevant with the 7-31 district of apo AIV) RWELALGRFWDYLRWVQTLSEQVQEEL (relevant with the 25-51 district of apo E) LSSQVTQELRALMDETMKELKELKAYKSELEEQLT (relevant with the 52-83 district of apo E) ARLSKELQAAQARLGADMEDVCGRLV (relevant with the 91-116 district of apo E) VRLASHLRKLRKRLLRDADDLQKRLA (relevant with the 135-160 district of apoE) PLVEDMQRQWAGLVEKVQA (apo 267-285 E.27) MSTYTGIFTDQVLSVLK (relevant with the 60-76 district of apo CII) LLSFMQGYMKHATKTAKDALSS (relevant with the 8-29 district of apo CIII)	1031 1032 1033 1034 1035 1036 1037 1038 1039

[0191] other exemplary G ^*Peptide is referring to table 17.

[0192] other exemplary G of table 17. ^*Peptide.

Peptide	SEQ ID NO
		Ac-Lys-Trp-Ile-Tyr-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Leu-Arg-Thr-Glu-Gly-NH 2	1040
Ac-Lys-Trp-Phe-Tyr-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Leu-Arg-Thr-Glu-Gly-NH 2	1041
		Ac-Lys-Trp-Leu-Tyr-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Leu-Arg-Thr-Glu-Gly-NH 2	1042
Ac-Lys-Trp-Val-Tyr-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Leu-Arg-Thr-Glu-Gly-NH 2	1043
		Ac-Lys-Tyr-Ile-Trp-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Leu-Arg-Thr-Glu-Gly-NH 2	1044
Ac-Lys-Trp-Ile-Tyr-His-phe-Thr-Glu-Gly-Ser-Thr-Asp-Leu-Arg-Thr-Glu-Gly-NH 2	1045
		Ac-Lys-Trp-Phe-Tyr-His-Ile-Thr-Glu-Gly-Ser-Thr-Asp-Leu-Arg-Thr-Glu-Gly-NH 2	1046
Ac-Lys-Trp-Leu-Tyr-His-Val-Thr-Glu-Gly-Ser-Thr-Asp-Leu-Arg-Thr-Glu-Gly-NH 2	1047
		Ac-Lys-Trp-Val-Tyr-His-Tyr-Thr-Glu-Gly-Ser-Thr-Asp-Leu-Arg-Thr-Glu-Gly-NH 2	1048
Ac-Lys-Tyr-Ile-Trp-His-Phe-Thr-Glu-Gly-Ser-Thr-Asp-Leu-Arg-Thr-Glu-Gly-NH 2	1049
		Ac-Lys-Tyr-Ile-Trp-His-Ile-Thr-Glu-Gly-Ser-Thr-Asp-Leu-Arg-Thr-Glu-Gly-NH 2	1050
Ac-Lys-Tyr-Ile-Trp-His-Val-Thr-Glu-Gly-Ser-Thr-Asp-Leu-Arg-Thr-Glu-Gly-NH 2	1051
		Ac-Lys-Tyr-Ile-Trp-His-Tyr-Thr-Glu-Gly-Ser-Thr-Asp-Leu-Arg-Thr-Glu-Gly-NH 2	1052
Ac-Lys-Phe-Ile-Trp-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Leu-Arg-Thr-Glu-Gly-NH 2	1053
		Ac-Lys-Leu-Ile-Trp-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Leu-Arg-Thr-Glu-Gly-NH 2	1054
Ac-Lys-Ile-Ile-Trp-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Leu-Arg-Thr-Glu-Gly-NH 2	1055
		Ac-Lys-Tyr-Ile-Trp-Phe-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Leu-Arg-Thr-Glu-Gly-NH 2	1056
Ac-Lys-Trp-Ile-Tyr-phe-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Leu-Arg-Thr-Glu-Gly-NH 2	1057
		Ac-Lys-Trp-Ile-Tyr-Leu-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Leu-Arg-Thr-Glu-Gly-NH 2	1058
Ac-Lys-Trp-Ile-Tyr-His-Phe-Thr-Glu-Gly-Ser-Thr-Asp-Leu-Arg-Thr-Glu-Gly-NH 2	1059
		Ac-Lys-Trp-Ile-Tyr-His-Tyr-Thr-Glu-Gly-Ser-Thr-	1060

Asp-Leu-Arg-Thr-Glu-Gly-NH 2
		Ac-Lys-Trp-Ile-Tyr-His-Ile-Thr-Glu-Gly-Ser-Thr-Asp-Leu-Arg-Thr-Glu-Gly-NH 2	1061
Ac-Lys-Trp-Ile-Tyr-His-Leu-Ser-Glu-Gly-Ser-Thr-Asp-Leu-Arg-Thr-Glu-Gly-NH 2	1062
		Ac-Lys-Trp-Ile-Tyr-His-Leu-Thr-Asp-Gly-Ser-Thr-Asp-Leu-Arg-Thr-Glu-Gly-NH 2	1063
Ac-Lys-Trp-Ile-Tyr-His-Leu-Thr-Glu-Gly-Thr-Ser-Asp-Leu-Arg-Thr-Glu-Gly-NH 2	1064
		Ac-Lys-Trp-Ile-Tyr-His-Leu-Thr-Glu-Gly-Ser-Thr-Glu-Leu-Arg-Thr-Glu-Gly-NH 2	1065
Ac-Lys-Trp-Ile-Tyr-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Phe-Arg-Thr-Glu-Gly-NH 2	1066
		Ac-Lys-Trp-Ile-Tyr-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Tyr-Arg-Thr-Glu-Gly-NH 2	1067
Ac-Lys-Trp-Ile-Tyr-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Ile-Arg-Thr-Glu-Gly-NH 2	1068
		Ac-Lys-Trp-Ile-Tyr-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Val-Arg-Thr-Glu-Gly-NH 2	1069
Ac-Lys-Trp-Ile-Tyr-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Leu-Lys-Thr-Glu-Gly-NH 2	1070
		Ac-Lys-Trp-Ile-Tyr-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Leu-Arg-Ser-Glu-Gly-NH 2	1071
Ac-Lys-Trp-Ile-Tyr-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Leu-Arg-Thr-Asp-Gly-NH 2	1072
		Ac-Lys-Trp-Ile-Tyr-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Ile-Lys-Thr-Glu-Gly-NH 2	1073
Ac-Lys-Trp-Ile-Tyr-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Ile-Arg-Ser-Glu-Gly-NH 2	1074
		Ac-Lys-Trp-Ile-Tyr-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Ile-Lys-Ser-Glu-Gly-NH 2	1075
Ac-Lys-Trp-Ile-Tyr-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Ile-Lys-Ser-Asp-Gly-NH 2	1076
		Ac-Arg-Trp-Ile-Tyr-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Leu-Arg-Thr-Glu-Gly-NH 2	1077
Ac-Arg-Tyr-Ile-Trp-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Ile-Arg-Thr-Glu-Gly-NH 2	1078
		Ac-Arg-Trp-Ile-Tyr-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Ile-Arg-Thr-Asp-Gly-NH 2	1079
Ac-Arg-Trp-Ile-Phe-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Ile-Arg-Thr-Glu-Gly-NH 2	1080
		Ac-Arg-Trp-Ile-Tyr-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Leu-Lys-Thr-Glu-Gly-NH 2	1081
Ac-Arg-Trp-Ile-Tyr-His-Leu-Thr-Asp-Gly-Ser-Thr-Asp-Ile-Arg-Thr-Glu-Gly-NH 2	1082
		Ac-Arg-Trp-Ile-Tyr-His-Leu-Thr-Asp-Gly-Ser-Thr-Asp-Leu-Arg-Thr-Glu-Gly-NH 2	l083
Ac-Arg-Trp-Ile-Tyr-Phe-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Ile-Arg-Thr-Glu-Gly-NH 2	l084
		Ac-Arg-Trp-Ile-Tyr-Phe-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Leu-Arg-Thr-Glu-Gly-NH 2	1085
Ac-Lys-Trp-Phe-Tyr-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Phe-Arg-Thr-Glu-Gly-NH 2	1086
		Ac-Arg-Trp-Phe-Tyr-His-Leu-Thr-Glu-Gly-Ser-Thr-	1087

Asp-Leu-Arg-Thr-Glu-Gly-NH 2
		Ac-Lys-Trp-Ile-Phe-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Ile-Arg-Thr-Asp-Gly-NH 2	1088
Ac-Arg-Trp-Ile-Tyr-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Ile-Arg-Thr-Asp-Gly-NH 2	1089
		Ac-Arg-Trp-Ile-Tyr-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Leu-Arg-Thr-Asp-Gly-NH 2	1090
Ac-Lys-Trp-Ile-Tyr-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Ile-Lys-Thr-Glu-Gly-NH 2	1091
		Ac-Lys-Trp-Ile-Tyr-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Ile-Lys-Thr-Asp-Gly-NH 2	1092
Ac-Lys-Trp-Ile-Tyr-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Phe-Lys-Thr-Glu-Gly-NH 2	1093
		Ac-Lys-Trp-Ile-Tyr-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Tyr-Lys-Thr-Glu-Gly-NH 2	1094
Ac-Lys-Trp-Ile-Tyr-His-Leu-Thr-Glu-Gly-Ser-Thr-Asp-Ile-Arg-Thr-Glu-Gly-NH 2	1095
		Ac-Lys-Trp-Phe-Tyr-His-Phe-Thr-Glu-Gly-Ser-Thr-Asp-Leu-Arg-Thr-Glu-Gly-NH 2	1096
Ac-Arg-Trp-Phe-Tyr-His-Phe-Thr-Glu-Gly-Ser-Thr-Asp-Leu-Arg-Thr-Glu-Gly-NH 2	1097
		Ac-Lys-Trp-Phe-Tyr-His-Phe-Thr-Glu-Gly-Ser-Thr-Asp-Phe-Arg-Thr-Glu-Gly-NH 2	1098
Ac-Lys-Trp-Phe-Tyr-His-Phe-Thr-Asp-Gly-Ser-Thr-Asp-Ile-Arg-Thr-Glu-Gly-NH 2	1099
		Ac-Arg-Trp-Phe-Tyr-His-Phe-Thr-Glu-Gly-Ser-Thr-Asp-Leu-Arg-Thr-Glu-Gly-NH 2	1100
Ac-Arg-Trp-Phe-Tyr-His-Phe-Thr-Glu-Gly-Ser-Thr-Asp-Phe-Arg-Thr-Glu-Gly-NH 2	1101
		Ac-Arg-Trp-Phe-Tyr-His-Phe-Thr-Glu-Gly-Ser-Thr-Asp-Phe-Arg-Thr-Asp-Gly-NH 2	1102
Ac-Glu-Lys-Cys-Val-Glu-Glu-Phe-Lys-Ser-Leu-Thr-Ser-Cys-Leu-Asp-Ser-Lys-Ala-phe-NH 2	1103
		Ac-Asp-Lys-Cys-Val-Glu-Glu-phe-Lys-Ser-Leu-Thr-Ser-Cys-Leu-Asp-Ser-Lys-Ala-Phe-NH 2	1104
Ac-Glu-Lys-Cys-Val-Asp-Glu-Phe-Lys-Ser-Leu-Thr-Ser-Cys-Leu-Asp-Ser-Lys-Ala-Phe-NH 2	1105
		Ac-Glu-Lys-Cys-Val-Glu-Asp-Phe-Lys-Ser-Leu-Thr-Ser-Cys-Leu-Asp-Ser-Lys-Ala-Phe-NH 2	1106
Ac-Glu-Arg-Cys-Val-Glu-Glu-Phe-Lys-Ser-Leu-Thr-Ser-Cys-Leu-Asp-Ser-Lys-Ala-Phe-NH 2	1107
		Ac-Asp-Lys-Cys-Val-Asp-Asp-Phe-Lys-Ser-Leu-Thr-Ser-cys-Leu-Asp-Ser-Lys-Ala-Phe-NH 2	1108
Ac-Asp-Arg-Cys-Val-Glu-Glu-Phe-Lys-Ser-Leu-Thr-Ser-Cys-Leu-Asp-Ser-Lys-Ala-Phe-NH 2	1109
		Ac-Glu-Arg-Cys-Val-Asp-Asp-Phe-Lys-Ser-Leu-Thr-Ser-Cys-Leu-Asp-Ser-Lys-Ala-Phe-NH 2	1110
Ac-Glu-Lys-Cys-Val-Glu-Glu-Phe-Lys-Ser-Phe-Thr-Ser-Cys-Leu-Asp-Ser-Lys-Ala-phe-NH 2	1111
		Ac-Glu-Lys-Cys-Val-Glu-Glu-Phe-Lys-Ser-Ile-Thr-Ser-Cys-Leu-Asp-Ser-Lys-Ala-phe-NH 2	1112
Ac-Glu-Lys-Cys-Val-Glu-Glu-Phe-Lys-Ser-Val-Thr-Ser-Cys-Leu-Asp-Ser-Lys-Ala-Phe-NH 2	1113
		Ac-Glu-Arg-Cys-Val-Glu-Glu-Phe-Lys-Ser-Tyr-Thr-	1114

Ser-Cys-Leu-Asp-Ser-Lys-Ala-Phe-NH 2
		Ac-Glu-Arg-Cys-Val-Glu-Glu-Phe-Lys-Ser-Phe-Thr-Ser-Cys-Leu-Asp-Ser-Lys-Ala-Phe-NH 2	1115
Ac-Glu-Arg-Cys-Val-Glu-Glu-Phe-Lys-Ser-Ile-Thr-Ser-Cys-Leu-Asp-Ser-Lys-Ala-Phe-NH 2	1116
		Ac-Glu-Arg-Cys-Val-Glu-Glu-Phe-Lys-Ser-Val-Thr-Ser-Cys-Leu-Asp-Ser-Lys-Ala-Phe-NH 2	1117
Ac-Glu-Arg-Cys-Val-Glu-Glu-Phe-Lys-Ser-Tyr-Thr-Ser-Cys-Leu-Asp-Ser-Lys-Ala-Phe-NH 2	1118
		Ac-Glu-Lys-Cys-Val-Glu-Glu-Phe-Lys-Ser-Phe-Thr-Thr-Cys-Leu-Asp-Ser-Lys-Ala-Phe-NH 2	1119
Ac-Glu-Lys-Cys-Val-Glu-Glu-Phe-Lys-Ser-Ile-Ser-Ser-Cys-Leu-Asp-Ser-Lys-Ala-Phe-NH 2	1120
		Ac-Glu-Lys-Cys-Val-Glu-Glu-Phe-Lys-Ser-Val-Ser-Thr-Cys-Leu-Asp-Ser-Lys-Ala-Phe-NH 2	1121
Ac-Glu-Lys-Cys-Val-Glu-Glu-Phe-Lys-Ser-Tyr-Thr-Ser-Cys-Leu-Asp-Ser-Lys-Ala-Phe-NH 2	1122
		Ac-Glu-Lys-Cys-Val-Glu-Glu-Phe-Lys-Ser-Phe-Thr-Thr-Cys-Leu-Asp-Ser-Lys-Ala-Phe-NH 2	1123
Ac-Glu-Lys-Cys-Val-Glu-Glu-Phe-Lys-Ser-Phe-Ser-Ser-Cys-Leu-Asp-Ser-Lys-Ala-Phe-NH 2	1124
		Ac-Glu-Lys-Cys-Val-Glu-Glu-Phe-Lys-Ser-Phe-Thr-Ser-Cys-Leu-Asp-Ser-Lys-Ala-Phe-NH 2	1125
Ac-Glu-Lys-Cys-Val-Glu-Glu-Phe-Lys-Ser-Phe-Thr-Ser-Cys-Leu-Asp-Ser-Lys-Ala-Phe-NH 2	1126
		Ac-Glu-Lys-Cys-Val-Glu-Glu-Phe-Lys-Ser-Phe-Thr-Ser-Cys-Leu-Asp-Ser-Lys-Ala-Phe-NH 2	1127
Ac-Glu-Lys-Cys-Val-Glu-Glu-Phe-Lys-Ser-Phe-Thr-Ser-Cys-Phe-Asp-Ser-Lys-Ala-Phe-NH 2	1128
		Ac-Glu-Lys-Cys-Val-Glu-Glu-Phe-Lys-Ser-Phe-Thr-Ser-Cys-Phe-Glu-Ser-Lys-Ala-Phe-NH 2	1129
Ac-Glu-Lys-Cys-Val-Glu-Glu-Phe-Lys-Ser-Phe-Thr-Ser-Cys-Leu-Glu-Ser-Lys-Ala-Phe-NH 2	1130
		Ac-Glu-Lys-Cys-Val-Glu-Glu-Phe-Lys-Ser-Phe-Thr-Ser-Cys-Ile-Asp-Ser-Lys-Ala-Phe-NH 2	1131
Ac-Glu-Lys-Cys-Val-Glu-Glu-Leu-Lys-Ser-Phe-Thr-Ser-Cys-Phe-Asp-Ser-Lys-Ala-Phe-NH 2	1132
		Ac-Asp-Lys-Cys-Val-Glu-Glu-phe-Lys-Ser-Phe-Thr-Ser-Cys-Phe-Asp-Ser-Lys-Ala-Phe-NH 2	1133
Ac-Asp-Lys-Cys-Val-Glu-Glu-Phe-Lys-Ser-Phe-Thr-Ser-Cys-Phe-Glu-Ser-Lys-Ala-Phe-NH 2	1134
		Ac-Glu-Arg-Cys-Val-Glu-Glu-phe-Lys-Ser-Phe-Thr-Ser-Cys-Phe-Asp-Ser-Lys-Ala-Phe-NH 2	1135
Ac-Glu-Lys-Cys-Phe-Glu-Glu-Phe-Lys-Ser-Phe-Thr-Ser-Cys-Phe-Asp-Ser-Lys-Ala-Phe-NH 2	1136
		Ac-Glu-Lys-Cys-Phe-Glu-Glu-Phe-Lys-Ser-Phe-Thr-Ser-Cys-Phe-Glu-Ser-Lys-Ala-Phe-NH 2	1137
Ac-Glu-Lys-Cys-Val-Glu-Glu-phe-Lys-Ser-Phe-Ser-Ser-Cys-Phe-Glu-Ser-Lys-Ala-Phe-NH 2	1138
		Ac-Glu-Lys-Cys-Val-Glu-Glu-Phe-Lys-Ser-Phe-Gln-Ser-Cys-Phe-Asp-Ser-Lys-Ala-Phe-NH 2	1139
Ac-Glu-Lys-Cys-Phe-Glu-Glu-Phe-Lys-Ser-Phe-Gln-Ser-Cys-Phe-Asp-Ser-Lys-Ala-Phe-NH 2	1140
		Ac-Glu-Lys-Cys-Val-Glu-Glu-Phe-Lys-Gln-Phe-Thr-	1141

Ser-cys-Phe-Asp-Ser-Lys-Ala-Phe-NH 2
		Ac-Glu-Lys-Cys-Val-Glu-Glu-Phe-Lys-Gln-Leu-Thr-Ser-Cys-Leu-Asp-Ser-Lys-Ala-Phe-NH 2	1142
Ac-Glu-Lys-Cys-Phe-Glu-Glu-Phe-Lys-Ser-Phe-Gln-Ser-Cys-Leu-Asp-Ser-Lys-Ala-Phe-NH 2	1143
		Ac-Glu-Lys-Cys-Val-Glu-Glu-Phe-Lys-Gln-phe-Thr-Ser-Cys-Phe-Asp-Ser-Lys-Ala-Phe-NH 2	1144
Ac-Glu-Lys-Cys-Val-Glu-Glu-Phe-Lys-Ser-Phe-Thr-Ser-Cys-Phe-Glu-Ser-Lys-Ala-Phe-NH 2	1145
		Ac-Glu-Arg-Cys-Phe-Glu-Glu-Phe-Lys-Ser-phe-Thr-Ser-Cys-Phe-Asp-Ser-Lys-Ala-Phe-NH 2	1146
Ac-Asp-Lys-Cys-Phe-Glu-Glu-Phe-Lys-Ser-Phe-Thr-Ser-Cys-Phe-Asp-Ser-Lys-Ala-Phe-NH 2	1147
		Ac-Glu-Arg-Cys-Val-Glu-Glu-Phe-Lys-Ser-Leu-Thr-Ser-Cys-Leu-Glu-Ser-Lys-Ala-Phe-NH 2	1148
Ac-Glu-Lys-Cys-Val-Glu-Glu-Phe-Lys-Ser-Leu-Thr-Ser-Cys-Leu-Asp-Ser-Lys-Phe-Phe-NH 2	1149
		Ac-Glu-Lys-Cys-Phe-Glu-Glu-Phe-Lys-Ser-phe-Thr-Ser-Cys-Phe-Asp-Ser-Lys-Phe-Phe-NH 2	1150
Ac-Asp-Lys-Cys-Phe-Glu-Glu-Phe-Lys-Ser-Phe-Thr-Ser-Cys-Leu-Asp-Ser-Lys-Phe-Phe-NH 2	1151
		Ac-Asp-Lys-Cys-Phe-Glu-Glu-Phe-Lys-Ser-Phe-Thr-Ser-Cys-Leu-Glu-Ser-Lys-Phe-Phe-NH 2	1152
Ac-Asp-Lys-Cys-Phe-Glu-Glu-Leu-Lys-Ser-Phe-Thr-Ser-Cys-Leu-Asp-Ser-Lys-Phe-Phe-NH 2	1153
		Ac-Glu-Arg-Cys-Phe-Glu-Glu-Phe-Lys-Ser-Phe-Thr-Ser-Cys-Leu-Asp-Ser-Lys-Phe-Phe-NH 2	1154
Ac-Glu-Lys-Ala-Val-Glu-Glu-Phe-Lys-Ser-Phe-Thr-Ser-Cys-Leu-Asp-Ser-Lys-Ala-Phe-NH 2	1155
		Ac-Asp-Lys-Ala-Val-Glu-Glu-Phe-Lys-Ser-Phe-Thr-Ser-Cys-Leu-Asp-Ser-Lys-Phe-Phe-NH 2	1156
Ac-Glu-Lys-Ala-Val-Glu-Glu-Phe-Lys-Ser-Phe-Thr-Ser-Ala-Leu-Asp-Ser-Lys-Ala-Phe-NH 2	1157
		Ac-Asp-Lys-Ala-Val-Glu-Glu-Phe-Lys-Ser-Phe-Thr-Ser-Ala-Leu-Asp-Ser-Lys-Ala-Phe-NH 2	1158
Ac-Asp-Arg-Ala-Phe-Glu-Glu-Phe-Lys-Ser-Phe-Thr-Ser-Cys-Leu-Asp-Ser-Lys-Phe-Phe-NH 2	1159
		Ac-Asp-Arg-Ala-Phe-Glu-Glu-Phe-Lys-Ser-Phe-Thr-Ser-Ala-Leu-Asp-Ser-Lys-Phe-Phe-NH 2	1160
Ac-Asp-Lys-Cys-Phe-Glu-Glu-Phe-Lys-Ser-Phe-Thr-Ser-Cys-Phe-Glu-Ser-Lys-Phe-Phe-NH 2	1161
		Ac-Glu-Lys-Cys-Tyr-Glu-Glu-Phe-Lys-Ser-Phe-Thr-Ser-Cys-Leu-Asp-Ser-Lys-Phe-Phe-NH 2	1162
Ac-Asp-Lys-Cys-Trp-Glu-Glu-Phe-Lys-Ser-Phe-Thr-Ser-Cys-Leu-Asp-Ser-Lys-Phe-Phe-NH 2	1163
		Ac-Glu-Lys-Cys-Phe-Glu-Glu-Phe-Lys-Ser-Tyr-Thr-Ser-Cys-Leu-Asp-Ser-Lys-Phe-Phe-NH 2	1164
Ac-Glu-Lys-Cys-Phe-Glu-Glu-Phe-Lys-Ser-Trp-Thr-Ser-Cys-Leu-Asp-Ser-Lys-Phe-Phe-NH 2	1165
		Ac-Glu-Lys-Cys-Val-Glu-Glu-Phe-Lys-Ser-Trp-Thr-Ser-Cys-Leu-Asp-Ser-Lys-Ala-Phe-NH 2	1166
Ac-Asp-Lys-Cys-Phe-Glu-Glu-Phe-Lys-Ser-Trp-Thr-Ser-Cys-Leu-Asp-Ser-Lys-Ala-Phe-NH 2	1167

[0193] other suitable peptide includes but not limited to the peptide in the table 18.

[0194] table 18. has the exemplary peptides of improving hydrophobic phase.

Title	Sequence	SEQ ID NO
			V2W3A5F1017-D-4F	Ac-Asp-Val-Trp-Lys-Ala-Ala-Tyr-Asp-Lys-Phe-Ala-Glu-Lys-Phe-Lys-Glu-Phe-Phe-NH2	1168
V2W3F10-D-4F	Ac-Asp-Val-Trp-Lys-Ala-Phe-Tyr-Asp-Lys-Phe-Ala-Glu-Lys-Phe-Lys-Glu-Ala-Phe-NH2	1169
			W3-D-4F	Ac-Asp-Phe-Trp-Lys-Ala-Phe-Tyr-Asp-Lys-Val-Ala-Glu-Lys-Phe-Lys-Glu-Ala-Phe-NH2	1170

[0195] peptide described herein (V2W3A5F10,17-D-4F; V2W3F10-D-4F; W3-D-4F) more effective than original D-4F.

[0196] also have other suitable peptide to include but not limited to: P ¹-dimethyl tyrosine-D-Arg-Phe-Lys-P ²(SEQ ID NO:1171) and P ¹-dimethyl tyrosine-Arg-Glu-Leu-P ², P wherein ¹And P ²Be protecting group described herein.In certain embodiments, these peptides include but not limited to Boc-dimethyl tyrosine-D-Arg-Phe-Lys (OtBu) and Boc dimethyl tyrosine-Arg-Glu-Leu (OtBu).

[0197] in certain embodiments; peptide of the present invention comprises the peptide that contains aminoacid sequence LAEYHAK (SEQ ID NO:1172); perhaps comprise the peptide of being made up of aminoacid sequence LAEYHAK (SEQ ID NO:1172), this sequence comprises at least one D aminoacid and/or at least one or two terminal protecting groups.In certain embodiments, the present invention includes the peptide of one or more symptoms of improving inflammatory diseases, wherein this peptide: length range about 3 to about 10 aminoacid; Comprise and comprise the acidic amino acid alternate or the aminoacid sequence of basic amino acid in the sequence with aromatic amino acid or hydrophobic amino acid; Comprise hydrophobic side aminoacid or have the end amino acid of hydrophobic protecting group; Not that sequence LAEYHAK (SEQ IDNO:1173) comprises whole L aminoacid; Wherein peptide makes short scorching HDL be transformed into antiinflammatory HDL, and/or makes antiinflammatory HDL antiinflammatory more.

It is also noted that [0198] peptide cited in this paper table is not included all peptides.Use the instruction that this paper provided, can produce other suitable peptide (for example replacing or half conservative (for example D is replaced by E), extension, the disappearance etc. of replacing) routinely by conservative.For example, embodiment is used the truncate of any one or more peptide that SEQ ID No:1011-1039 identified.

[0199] long peptide also suits.Long peptide can complete formation G class amphipathic helix or G ^*The class amphipathic helix, perhaps the G amphipathic helix can form one or more domains of peptide.In addition, the present invention includes the polymer form of peptide.For example, cited peptide can be coupled at (directly or by joint (for example carbon atom joint or one or more aminoacid) coupling) with one or more aminoacid that interleave in each table of this paper.Suitable joint includes but not limited to proline (Pro-), Gly ₄Ser ₃(SEQ ID NO:1174) etc.For example, an exemplary polymer peptide of the present invention (is Ac-L-L-E-Q-L-N-E-Q-F-N-W-V-S-R-L-A-N-L-T-Q-G-E for (D-J336)-P-(D-J336) -P-L-L-E-Q-L-N-E-Q-F-N-W-V-S-R-L-A-N-L-T-Q-G-E-NH ₂, SEQ ID NO:1175).

[0200] the present invention comprises that also use comprises one or more G amphipathic helix territories or G ^*" heterozygosis " peptide of amphipathic helix territory and one or more category-A amphipathic helixs.Proper A class amphipathic helix peptide is referring to PCT publication No. WO 02/15923.For instance, such " heterozygosis " peptide (is Ac-L-L-E-Q-L-N-E-Q-F-N-W-V-S-R-L-A-N-L-T-Q-G-E for (D-J336)-Pro-(4F) -P-D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-NH ₂, SEQ ID NO:1176) etc.

[0201] use the instruction that this paper provided, the technical staff can carry out conventional the modification to produce other suitable apo J variant of the present invention and/or amphipathic G helical peptides and/or A helical peptides to the amphipathic helix peptide that is listed.For example, conventional conservative replace or half conservative replacement the (for example E replaces D) can carry out on existing aminoacid.Can use people's (1996) such as Palgunachari computational methods (Palgunachari etc. (1996) Arteriosclerosis, Thrombosis ， ﹠amp; Vascular Biol.16:328-338), predict the effect of various replacements to the lipid affinity of gained peptide.As long as all kinds of helical structures are guarded, then can or shorten the peptide lengthening.In addition, can replace so that the gained peptide comparatively is similar to the peptide that produces in curee's body.

[0202] in preferred embodiments; though peptide of the present invention utilizes naturally occurring aminoacid or naturally occurring D type aminoacid, exist in the replacement of aminoacid (for example methionine sulfoxide, methionine methyl sulfonium, nor-leucine, episilon amino caproic acid, 4-aminobutyric acid, tetrahydroisoquinoline-3-formic acid, 8-aminocaprylic acid, 4-aminobutyric acid, Lys (N (ε)-trifluoroacetyl group), α-diaminourea isopropylformic acid. etc.) is also included within non-natural.

[0203] can and/or estimate new peptide with the computational methods design.The amphipathic helix territory is identified and the computer program of classifying is that those skilled in the art are well-known that many methods are referring to (1992) J.Lipid Res.33:287-296 such as Jones).These programs include but not limited to helical wheel program (WHEEL or WHEEL/SNORKEL), spiral net program (HELNET, HELNET/SNORKEL, HELNET/Angle), helical wheel appendage (COMBO or COMBO/SNORKEL), spiral net appendage (COMNET, COMNET/SNORKEL, COMBO/SELECT, COMBO/NET), total wheel program (CONSENSUS, CONSENSUS/SNORKEL) supervisor.

F) blocking groups and D residue

[0204] though various peptide as herein described and/or aminoacid to can not having protecting group, in some embodiment (for example especially oral administration), they can have 1,2,3,4 or more a plurality of protecting group.Protecting group can with the C of peptide end and/or N end and/or link coupled with one or more inside residues (for example the one or more R groups on the composition aminoacid can be closed) that contain peptide.For example, in certain embodiments, arbitrary peptide as herein described can have the acetyl group of for example protecting the N end and/or the amide groups of protecting the C end.An example of this " dual " protection peptide is Ac-L-L-E-Q-L-N-E-Q-F-N-W-V-S-R-L-A-N-L-T-Q-G-E-NH ₂(SEQ ID NO:1011 has blocking groups), any in these protecting groups or two can slough and/or be replaced by another protecting group as herein described.

[0205] be not subjected under the situation of particular theory constraint, the present invention finds, sealing, and the sealing of subject peptide N end especially of the present invention and/or C end has greatly improved oral drug delivery, significantly increases the serum half life.

[0206] very many protecting groups are applicable to this purpose.These groups include but not limited to acetyl group, amide groups and alkyl, and wherein acetyl group and alkyl are particularly preferred for the protection of N end, and amide groups is preferred for the protection of C end.In some particularly preferred embodiment, protecting group includes but not limited to alkyl chain (in fatty acid), propeonyl, formoxyl and other group.Particularly preferred carboxyl-protecting group comprises that amide, ester and ether form protecting group.In a preferred embodiment, use acetyl group protection N end, use amide groups protection C end.These blocking groupses are strengthened the spiralization trend of peptide.Some particularly preferred blocking groups comprises the alkyl of all lengths, for example has formula CH ₃-(CH ₂) _nThe group of-CO-, wherein the scope of n is about 1 to about 20, and is preferred about 1 to about 16 or 18, more preferably from about 3 to about 13, and most preferably from about 3 to about 10.

[0207] in some particularly preferred embodiment, protecting group includes but not limited to alkyl chain (in fatty acid), propeonyl, formoxyl and other group.Particularly preferred carboxyl-protecting group comprises that amide, ester and ether form protecting group.In a preferred embodiment, use acetyl group protection N end, use amide groups protection C end.These blocking groupses are strengthened the spiralization trend of peptide.Some particularly preferred blocking groups comprises the alkyl of all lengths, for example has formula CH ₃-(CH ₂) _nThe group of-CO-, wherein the scope of n about 3 is to about 20, and preferred about 3 to about 16, and more preferably from about 3 to about 13, and most preferably from about 3 to about 10.

[0208] other protecting group includes but not limited to Fmoc; tertbutyloxycarbonyl (t-BOC); 9-fluorenes acetyl group; 1-fluorenes carboxyl; 9-fluorenes carboxyl; 9-Fluorenone-1-carboxyl; benzyloxycarbonyl; xanthyl (Xan); trityl (Trt); 4-methyl trityl (Mtt); 4-methoxyl group trityl (Mmt); 4-methoxyl group-2; 3; 6-trimethyl-benzenesulfonyl (Mtr); -2-sulfonyl (Mts); 4; 4-dimethoxy benzhydryl (Mbh); tosyl (Tos); 2; 2; 5; 7; 8-pentamethyl benzo dihydropyran-6-sulfonyl (Pmc); 4-methyl-benzyl (MeBzl); 4-methoxy-benzyl (MeOBzl); benzyloxy (BzlO); benzyl (Bzl); benzoyl (Bz); 3-nitro-2-pyridine sulfenyl (Npys); 1-(4; 4-dimethyl (dimentyl)-2; 6-dioxo cyclohexylidene (diaxocyclohexylidene)) ethyl (Dde); 2; the 6-dichloro benzyl (2,6-DiCl-Bzl); 2-chlorine benzyloxycarbonyl (2-Cl-Z); 2-bromo-benzyloxy-carbonyl (2-Br-Z); benzyloxymethyl (Bom); cyclohexyloxy (cHxO); tert-butoxy methyl (Bum); tert-butoxy (tBuO); the tert-butyl group (tBu); acetyl group (Ac) and trifluoroacetyl group (TFA).

[0209] as with these groups with comprise that the link coupled method of suitable residue of peptide of the present invention is (referring to (1991) Protective Groups in Organic Synthesis such as for example Greene, second edition, John Wiley﹠amp; Sons, Inc.Somerset, N.J.), protection/blocking groups is that those skilled in the art are well-known.In a preferred embodiment, for example, between synthesis stage, when peptide is in the resin, use acetic anhydride to finish acetylation.Select appropriate resin can reach the amide protective effect in synthetic.Between the synthesis stage of peptide described in this paper embodiment, use the rink amide resin.After synthetic the finishing, can all slough the temporary protection base on acid difunctionality aminoacid (for example Asp and Glu) and the basic amino acid Lys simultaneously, slough the hydroxyl on the Tyr.From the peptide that resin discharges, what obtain is that N holds protected one-tenth acetyl group, the protected one-tenth of carboxyl NH with acid treatment ₂, and all other protecting group is removed simultaneously.

[0210] in some particularly preferred embodiment, this peptide comprises one or more D type as herein described (dextrorotation rather than left-handed) aminoacid.In certain embodiments, at least two enantiomer aminoacid, more preferably at least 4 enantiomer aminoacid, most preferably at least 8 or 10 enantiomer aminoacid are " D " type aminoacid.In certain embodiments, peptide described herein is every an aminoacid, perhaps in addition each aminoacid (for example each enantiomer aminoacid) all be D type aminoacid.

[0211] in certain embodiments, at least 50% enantiomer aminoacid is " D " type, and more preferably at least 80% enantiomer aminoacid is " D " type, most preferably at least 90% or even all enantiomer aminoacid all be " D " type aminoacid.

G) peptide mimics

[0212] except that peptide described herein, also comprises simulating peptide.Peptide analogues usually is used for pharmaceuticals industry as having the non-peptide medicine that is similar to the template peptide nature.The type of these non-peptide compounds is called as " peptide mimics (peptide mimetics) " or " simulating peptide " (peptidomimetics) (Fauchere (1986) Adv.Drug Res.15:29; The 392nd page of Veber and Freidinger (1985) TINS; With (1987) J.Med.Chem.30:1229 such as Evans), modeling is researched and developed by the computerization molecule usually.The peptide mimics that is similar to the last useful peptide of treatment on the structure can be used for producing treatment or the preventive effect that is equal to.

[0213] in general, be similar to example polypeptide (routine SEQ ID NO:5 as shown in table 1) on the simulating peptide structure, but by means known in the art and described other method of list of references, one or more peptide key options are selected from following key displacement :-CH ₂NH-,-CH ₂S-,-CH ₂-CH ₂-,-CH=CH-(cis and trans) ,-COCH ₂-,-CH (OH) CH ₂-,-CH ₂SO-etc.Relevant list of references is referring to the 267th page of Spatola (1983), Chemistry andBiochemistry of Amino Acids, and Peptides, and Proteins, the B.Weinstein chief editor, Marcel Dekker, New York; Spatola (1983) Vega Data 1 (3) PeptideBackbone Modifications. (summary); Morley (1980) Trends Pharm Sci, 463-468 page or leaf (summary); Hudson etc. (1979) Int J Pept Prot Res 14:177-185 (CH ₂NH-, CH ₂CH ₂-); Spatola etc. (1986) Life Sci 38:1243-1249 (CH ₂-S); Hann, (1982) J Chem Soc Perkin Trans I 307-314 (CH-CH-, cis and trans); Almquist etc. (1980) J Med Chem.23:1392-1398 (COCH ₂-); Jennings-White etc. (1982) Tetrahedron Lett.23:2533 (COCH ₂-); Szeike etc., European application EP 45665 (1982) CA:97:39405 (1982) (CH (OH) CH ₂-); Holladay etc. (1983) Tetrahedron Lett24:4401-4404 (C (OH) CH ₂-); And Hruby (1982) Life Sci.31:189-199 (CH ₂-S-).

[0214] particularly preferred non-peptide bond is-CH ₂NH-.This peptide mimics may have important advantage in the polypeptide embodiment, comprise that for example product is more economical, chemical stability is better, pharmacological properties strengthens (half life, absorb, tire, effect etc.), antigenicity reduces, or the like.

[0215] in addition, the cyclic sequence of peptide described herein changes or comprises the constraint peptide (comprising the cyclisation peptide) of consensus sequence or basic identical consensus sequence variant, and available means known in the art produce (Rizo and Gierasch (1992) Ann.Rev.Biochem.61:387); For example add inner cysteine residues and can form the intramolecular disulfide bridge that makes the peptide cyclisation.

H) organic molecule

[0216] in certain embodiments, activating agent of the present invention comprises organic molecule, for example micromolecule described in the copending application USSN 60/600,925 (application on August 11st, 2004).In different embodiments, organic molecule is similar to tetrapeptide and the pentapeptide described in copending application USSN 10/649,378 (application on August 26th, 2003) and the USSN 60/494,449 (application on August 11st, 2003), in some cases, be the analogies of these peptides.

[0217] molecular weight of organic molecule of the present invention usually＜about 900 dalton.Usually molecule very easily is dissolved in ethyl acetate (concentration 〉=4mg/ml), also be dissolved in aqueous buffer solution during pH7.0 for example.

[0218] phospholipid (for example 1, the two myristoyls of 2--sn-glyceryl-3-phosphocholine (DMPC)) is contacted with organic molecule of the present invention under aqueous environments, cause the about 7.5nm of diameter (± 0.1nm) particulate formation usually.In addition, usually form the folded bilayer of buttress that double-deck size is about the about 2nm of spacing between 3.4-4.1nm, the folded middle bilayer of buttress.Also usually form the vesicle structure of about 38nm.In addition, when giving mammal the of the present invention minute period of the day from 11 p.m. to 1 a.m, can make HDL antiinflammatory and alleviate atherosclerosis and/or be one or more symptoms of other disease of feature more with the inflammatory reaction.

[0219] therefore, in certain embodiments, organic molecule is that improving mammiferous is the micromolecule of one or more symptoms of the pathology (for example atherosclerosis) of feature with the inflammatory reaction, wherein be dissolved in ethyl acetate during micromolecule concentration＞4mg/ml, be dissolved in aqueous buffer solution during pH7.0, when under aqueous environments, contacting with phospholipid, form the granule of the about 7.5nm of diameter, and form double-deck size be about 3.4-4.1nm, buttress folded in the folded bilayer of buttress of the about 2nm of spacing between the bilayer, molecular weight＜900 dalton.

[0220] in certain embodiments, this molecule has following structural:

P wherein ¹, P ², P ³And P ⁴Independently be selected from hydrophobic protecting group; R ¹And R ⁴Independently be selected from aminoacid R group; N, i, x, y and z are 0 or 1 independently, therefore if n and x are zero, and R then ¹Be hydrophobic group, if y and i are zero, R then ⁴Be hydrophobic group; R ²And R ³When pH7.0 acidic-group or basic group, if so R ²Be acidity, then R ³Be alkalescence, if R ²Be alkalescence, then R ³Be acidity; R ⁵If exist, then be selected from aromatic group, aliphatic group, positively charged group or electronegative group.In certain embodiments, R ²Or R ³For-(CH ₂) _j-COOH, wherein j=1,2,3 or 4, and/or R ²Or R ³For-(CH ₂) j-NH ₂, wherein j=1,2,3,4 or 5, perhaps R ²Or R ³For-(CH ₂) j-NH-C (=NH)-NH ₂, n=1,2,3 or 4 wherein.In certain embodiments, R ², R ³And R ⁵If when existing, be aminoacid R group.For example, in different embodiments, R ²And R ³Be aspartic acid R group, glutamic acid R group, lysine R group, histidine R group or arginine R group (for example listed in the table 1) independently.

[0221] in certain embodiments, R ¹Be selected from Lys R group, Trp R group, PheR group, Leu R group, Orn R group, pr a norLeu R group.In certain embodiments, R ⁴Be selected from Ser R group, Thr R group, Ile R group, Leu R group, norLeuR group, Phe R group or Tyr R group.

[0222] in different embodiments, x is 1, R ⁵Be aromatic group (for example Trp R group).

[0223] in different embodiments, at least one is 1 among n, x, y and the i, P ¹, P ², P ³And P ⁴If exist; then independently be selected from Polyethylene Glycol (PEG); acetyl group; amide groups; the alkyl of 3-20 carbon atom; fmoc; 9-fluorenes acetyl group; 1-fluorenes carboxyl; 9-fluorenes carboxyl; 9-Fluorenone-1-carboxyl; benzyloxycarbonyl; xanthyl (Xan); trityl (Trt); 4-methyl trityl (Mtt); 4-methoxyl group trityl (Mmt); 4-methoxyl group-2; 3; 6-trimethyl-benzenesulfonyl (Mtr); -2-sulfonyl (Mts); 4; 4-dimethoxy benzhydryl (Mbh); tosyl (Tos); 2; 2; 5; 7; 8-pentamethyl benzo dihydropyran-6-sulfonyl (Pmc); 4-methyl-benzyl (MeBzl); 4-methoxy-benzyl (MeOBzl); benzyloxy (BzlO); benzyl (Bzl); benzoyl (Bz); 3-nitro-2-pyridine sulfenyl (Npys); 1-(4; 4-dimethyl-2; 6-dioxo cyclohexylidene) ethyl (Dde); 2; the 6-dichloro benzyl (2,6-DiCl-Bzl); 2-chlorine benzyloxycarbonyl (2-Cl-Z); 2-bromo-benzyloxy-carbonyl (2-Br-Z); benzyloxymethyl (Bom); tertbutyloxycarbonyl (Boc); cyclohexyloxy (cHxO); tert-butoxy methyl (Bum); tert-butoxy (tBuO); the tert-butyl group (tBu); propyl group; butyl; amyl group; hexyl and trifluoroacetyl group (TFA).In certain embodiments, P ¹If exist, and/or P ²If exist, then independently be selected from Boc-, Fmoc-and nicotinoyl (Nicotinyl-), and/or P ³If exist and/or P ⁴If exist, then independently be selected from tBu and OtBu.

[0224] though above exemplified many protecting group (P ¹, P ², P ³, P ⁴), but this tabulation is exemplary and not restrictive.In view of the instruction that this paper provided, many other protection/blocking groupses also are well known to those skilled in the art.Can select for use these blocking groupses to make digestion minimum (for example being used for oral drug delivery) and/or increase absorptions/bioavailability (for example by mucous membrane surface intranasal delivery, anapnotherapy, rectally) and/or increase blood serum half life.In certain embodiments, protecting group can be used as excipient or provides as the component of excipient.

[0225] in certain embodiments, z is 0, and this molecule has following structural:

P wherein ¹, P ², P ³, P ⁴, R ¹, R ², R ³, R ⁴, n, x, y and i as mentioned above.

[0226] in certain embodiments, z is 0, and this molecule has following structural:

R wherein ¹, R ², R ³And R ⁴As mentioned above.

[0227] in one embodiment, this molecule has following structural:

[0228] in certain embodiments, the present invention includes micromolecule, and this micromolecule has following structural with one or more physiological properties described herein and/or functional character:

P wherein ¹, P ², P ³And P ⁴Independently be selected from aforesaid hydrophobic protecting group, n, x and y are 0 or 1 independently; J, k and l are 0,1,2,3,4 or 5 independently; R ²And R ³When pH7.0 acidic-group or basic group, if so R ²Be acidity, then R ³Be alkalescence, if R ²Be alkalescence, then R ³Be acidity.In certain preferred aspects, micromolecule is water-soluble; Micromolecular molecular weight＜about 900 dalton.In certain embodiments, n, x, y, j and l are 1; K is 4.

[0229] in certain embodiments, P ¹And/or P ²Be the aromatics protecting group.In certain embodiments, R ²And R ³Be aminoacid R group, for example, aforesaid R group.In different embodiments, at least one is 1 among n, x and the y, P ¹, P ², P ³And P ⁴If exist, then be protecting group independently, for example, aforesaid protecting group.In certain embodiments; if protecting group exists; then independently be selected from Polyethylene Glycol (PEG); acetyl group; amide groups; the alkyl of 3-20 carbon atom; Fmoc; 9-fluorenes acetyl group; 1-fluorenes carboxyl; 9-fluorenes carboxyl; 9-Fluorenone-1-carboxyl; benzyloxycarbonyl; xanthyl (Xan); trityl (Trt); 4-methyl trityl (Mtt); 4-methoxyl group trityl (Mmt); 4-methoxyl group-2; 3; 6-trimethyl-benzenesulfonyl (Mtr); -2-sulfonyl (Mts); 4; 4-dimethoxy benzhydryl (Mbh); tosyl (Tos); 2; 2; 5; 7; 8-pentamethyl benzo dihydropyran-6-sulfonyl (Pmc); 4-methyl-benzyl (MeBzl); 4-methoxy-benzyl (MeOBzl); benzyloxy (BzlO); benzyl (Bzl); benzoyl (Bz); 3-nitro-2-pyridine sulfenyl (Npys); 1-(4; 4-dimethyl-2; 6-dioxo cyclohexylidene) ethyl (Dde); 2; the 6-dichloro benzyl (2,6-DiCl-Bzl); 2-chlorine benzyloxycarbonyl (2-Cl-Z); 2-bromo-benzyloxy-carbonyl (2-Br-Z); benzyloxymethyl (Bom); tertbutyloxycarbonyl (Boc); cyclohexyloxy (cHxO); tert-butoxy methyl (Bum); tert-butoxy (tBuO); the tert-butyl group (tBu); propyl group; butyl; amyl group; hexyl and trifluoroacetyl group (TFA).In certain embodiments, P ¹If exist, and/or P ²If exist, then independently be selected from Boc-, Fmoc-and nicotinoyl (Nicotinyl-), and/or P ³If exist, and/or P ⁴If exist, then independently be selected from tBu and OtBu.

III. the functional examination of activating agent

[0230] this paper by each structural formula (for example following formula I) and/or by concrete sequence description be used for some activating agent of the inventive method.In certain embodiments, the preferred activating agent of the present invention is a feature with following one or more functional characters:

1. make short scorching HDL be transformed into antiinflammatory HDL or make antiinflammatory HDL antiinflammatory more;

2. reduce by the inductive monocyte chemotactic activity of the LDL that arterial wall cell produced;

3. formation and the circulation of β HDL before stimulating;

4. improve the HDL cholesterol; And/or

5. strengthen HDL paraoxonase activity.

[0231] can easily determine activity specific agent disclosed herein and/or one or more required activity of the corresponding activating agent of various structural formula described herein.

[0232] each screening technique of these functional characters is well known to those skilled in the art.Specifically, be noted that monocyte chemotactic activity, HDL cholesterol and the active algoscopy of HDLHDL paraoxonase are referring to PCT/US01/26497 (WO2002/15923).

IV. peptide preparation

[0233] peptide used in the present invention can adopt standard chemical peptide synthetic technology to carry out chemosynthesis, if perhaps especially peptide do not comprise " D " amino acid residue, then can carry out recombinant expressed.In certain embodiments, in addition the peptide that comprises " D " amino acid residue also can carry out recombinant expressed.Carry out when recombinant expressed at polypeptide, supply with biological one or more aminoacid with the D type at the environment special secondary school that host living beings (for example antibacterial, plant, fungal cell etc.) is cultivated.Therefore peptide recombinant expressed in this system has mixed these D aminoacid.

[0234] in preferred embodiments, by many solution well known by persons skilled in the art mutually or any of solid-phase peptide synthetic technology carry out the chemosynthesis of peptide.In the solid phase synthesis, the C terminal amino acid of sequence is connected with insoluble support, adds successively subsequently that remaining aminoacid is the synthetic method for optimizing of chemiluminescent polypeptide of the present invention in the sequence.The technology of solid phase synthesis is well known to those skilled in the art, referring to for example Barany and Merrifield (1963) Solid-Phase Peptide Synthesis; The 3-284 page or leaf, The Peptides:Analysis, Synthesis, Biology. the 2nd roll up: Special Methods in Peptide Synthesis, (1984) Solid Phase Peptide Synthesis such as (1963) J.Am.Chem.Soc.85:2149-2156 such as Part A.Merrifield and Stewart, second edition, Pierce Chem.Co.Rockford, I11.

[0235] in certain embodiments, the solid phase method of peptide synthesis is used benzhydrylamine resin (Beckman Bioproducts, 0.59mmol NH ₂/ g resin) carries out the synthetic of peptide as solid support.(for example tert-butyl group carbonyl-Phe) is connected with solid support by 4-(oxygen ylmethyl) phenylacetyl group the COOH terminal amino acid.This is than the stable key of benzyl ester bond commonly used, yet the finished product peptide still can fall by hydrocrack.Be used for this purpose with formic acid as the transfer hydrogenation of hydrogen donor.The analysis of synthetic used detailed protocol of peptide and synthetic peptide is referring to (1985) J.Biol.Chem.260 (16) such as Anantharamaiah: the supplementary issue of reprinting books in a reduce format that 10248-10255 gives as an addition.

[0236] be noted that in the chemosynthesis of peptide, especially comprise the amino acid whose peptide of D synthetic in, except required full length product, the synthetic peptide that produces many truncates usually.Purification process (for example HPLC) causes the loss of full length product very big usually.

[0237] the present invention finds, in D peptide (for example D-4) is synthetic, purification during the peptide of microscler formula in order to avoid damage, can dialyse and use mixture, thereby in the end remove in the HPLC purification.This mixture loses about 50% (for example protein/weight) that highly purified product is tired, but mixture contains the peptide of having an appointment more than 6 times, and therefore bigger gross activity is arranged.

V. pharmaceutical preparation and device

A) pharmaceutical preparation

[0238] in order to implement method of the present invention, one or more activating agents of the present invention is given for example to be diagnosed as atherosclerotic one or more symptoms of trouble or atherosclerosis arranged and/or the individuality of various other risk of pathologies described herein.Activating agent can " natural " form, perhaps gives with forms such as salt, ester, amide, prodrug, derivants if needed, and it is suitable that precondition is that salt, ester, amide, prodrug or derivant are that the pharmacology goes up, and that is to say it is effective in the methods of the invention.Can be with standard method and for example March (1992) Advanced Organic Chemistry known to the synthetic organic chemistry those skilled in the art; Reactions, Mechanisms and Structure, the 4th edition, the described method of N.Y.Wiley-Interscience, salt, ester, amide, prodrug and other derivant of preparation activating agent.

[0239] for example, prepare acid-addition salts with conventional method by free alkali, this generally includes and suitable acid reaction.In general, the alkali form of medicine is dissolved in polar organic solvent for example methanol or ethanol, and to wherein adding acid.Gained salt or precipitation or can add the less solvent of polarity and separate out.The appropriate acid that is used to prepare acid-addition salts comprises organic acid, for example acetic acid, propanoic acid, glycolic, acetone acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, salicylic acid etc., and mineral acid, for example hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid etc.Acid-addition salts can be by being transformed into free alkali with suitable alkali treatment again.The acid-addition salts of the particularly preferred activating agent of this paper is a halide salts, for example can prepare with hydrochloric acid or hydrobromic acid.On the contrary, use pharmaceutically acceptable alkali (for example sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, trimethylamine etc.) preparation activating agent basic salt preparation of the present invention in a similar manner.Particularly preferred basic salt comprises alkali metal salt, for example sodium salt and mantoquita.

[0240] preparation of ester generally includes and is present in the functionalized of interior hydroxyl of drug molecular structure and/or carboxyl.The acyl substituted derivant of the normally free alcohol radical of ester (promptly from the part of formula RCOOH carboxylic acid derivatives, wherein R is alkyl, is preferably low alkyl group).If needed, can make ester be transformed into free acid again with conventional hydrogenolysis or Hydrolyze method.

[0241] also can use those skilled in the art's known technology or the described technology of relevant documents and materials, preparation amide and prodrug.For example, amide can be prepared by ester with suitable amine reactant, is perhaps reacted by acid anhydride or acid chloride and ammonia or low-grade alkylamine to prepare.Usually by with cause chemical compound up to modify the covalently bound prodrug for preparing of part that just has therapeutic activity through individual metabolic system.

[0242] activating agent that this paper identified is used for parenteral, part, oral, nose (or other suck with), rectum or topical (for example aerosol or percutaneous inhalant), with prophylactic treatment and/or one or more pathology/indications as herein described of therapeutic treatment (for example atherosclerosis and/or its symptom).Pharmaceutical composition can give by multiple unit dosage forms, and this depends on medication.Suitable unit dosage forms includes but not limited to powder, tablet, pill, capsule, lozenge, suppository, patch, nasal mist, injection, implantation slow releasing preparation, lipid complex etc.

[0243] activating agent of the present invention is mixed and made into the pharmacology compositions mutually with pharmaceutically acceptable carrier (excipient) usually.Pharmaceutically acceptable carrier can comprise one or more physiologically acceptable chemical compounds, and this chemical compound plays for example stable composition or increase or reduces the effect that activating agent absorbs.Physiologically acceptable chemical compound can comprise for example saccharide (for example glucose, sucrose or glucosan), antioxidant (for example ascorbic acid or glutathion), chelating agen, low molecular weight protein, protection and absorption enhancer (for example compositions of lipid, reduction activating agent clearance rate or hydrolysis) or excipient or other stabilizing agent and/or buffer agent.

[0244] other physiologically acceptable chemical compound comprises wetting agent, emulsifying agent, dispersant or is used in particular for preventing the antiseptic of growth of microorganism or effect.Various antiseptic are well-known, comprise for example phenol and ascorbic acid.It will be understood by those skilled in the art that pharmaceutically acceptable carrier, for example route of administration of activating agent and the concrete physicochemical property of activating agent are depended in the selection that comprises physiologically acceptable chemical compound.

[0245] excipient is preferably aseptic, does not contain unwanted material usually.These compositionss can be sterilized with well-known conventional sterilization technology.

[0246] in therapeutic is used, compositions of the present invention suffered from one or more symptoms of one or more pathology described herein or the patient of one or more risk of pathologies described herein is arranged, consumption is enough to prevent and/or cures and/or prevent or suppress described disease and/or its complication to small part.Be enough to realize that the amount of this purpose is defined as " treatment effective dose ".The effective dose that is used for this purposes depends on the order of severity of disease and the general situation of patient health.Tolerate situation according to required dosage and frequency and patient, can give or repeatedly give compositions by single.In any case, compositions should provide the activating agent of the dosage form of the present invention of sufficient dosage, to treat patient (improving one or more symptoms) effectively.

[0247] concentration of activating agent can significantly change, and will mainly select according to liquid volume, viscosity, body weight etc. according to selected concrete administering mode and patient's needs.Yet selection provides the concentration of following dosage range usually: about 0.1mg/kg/ days or 1mg/kg/ days to about 50mg/kg/ days, higher sometimes.Typical the about 3mg/kg/ of dosage range days to about 3.5mg/kg/ days, preferably about 3.5mg/kg/ days to about 7.2mg/kg/ days, more preferably from about 7.2mg/kg/ days to about 11.0mg/kg/ days, most preferably from about 11.0mg/kg/ days to about 15.0mg/kg/ days.In certain preferred aspects, the about 10mg/kg/ of dosage range days to about 50mg/kg/ days.In certain embodiments, the about 20mg of dosage range is to about 50mg, every day twice oral administration.It will be appreciated that this dosage can change so that to individual curee or the curee's of colony therapeutic scheme optimization.

[0248] in certain preferred aspects, activating agent oral administration of the present invention gives (for example tablet) or according to standard method well known to those skilled in the art, as injection.In other embodiment preferred, peptide of the present invention also can be used conventional percutaneous delivery system by dermal delivery, i.e. percutaneous " patch ", and wherein activating agent is generally comprised within the lamellar structure, and this lamellar structure is attached on the skin as drug delivery systems.In this structure, pharmaceutical composition comprises in the medicine layer or " storage storehouse " on the backing layer usually.It will be appreciated that the term of this paper " storage storehouse " is meant that some finally can be delivered to " active component " of skin surface.For example, " storage storehouse " can be included in active component in the adhesive of patch backing layer, the active component in perhaps any multiple different skeleton preparations well known by persons skilled in the art.Patch can contain single storage storehouse, perhaps can contain a plurality of storages storehouse.

[0249] in one embodiment, the storage storehouse comprises the polymer backbone of pharmaceutically acceptable contact sizing material, as in passing the medicine process system being pasted on the skin.The example of suitable skin contact sizing material includes but not limited to polyethylene, polysiloxanes, polyisobutylene, polyacrylate, polyurethane etc.Perhaps pastille storage storehouse and contact skin adhesive with each independently the medicine layer exist, therefore storage storehouse adhesive down can be aforesaid polymer backbone, perhaps can be that liquid or hydrogel are store the storehouse, perhaps can be some other form.Be used as the backing layer of device upper surface in these lamellas, be preferably used as the main member of " patch ", and provide suitable elasticity for device.The selected material that is used for backing layer is impermeable for activating agent basically preferably, also has any other material.

[0250] being used for the part passs other preferred dosage form of medicine and includes but not limited to ointment and ointment.Ointment is common semi-solid preparation based on vaseline or other petroleum derivative.The ointment that contains selected activating agent is generally viscous liquid or semi-solid Emulsion, usually is oil-in-water or water in oil.Emulsifiable paste matrix normally can be washed, and contains oil phase, emulsifying agent and water.Oil phase claims " interior " phase sometimes again, is made up of vaseline and aliphatic alcohol (for example spermol or stearyl alcohol) usually; Although dispensable, the water volume surpasses oil phase usually, contains wetting agent usually.Emulsifying agent in the cream preparation is non-ionic surface active agent, anion surfactant, cationic surfactant or amphoteric surfactant normally.As understood by one of ordinary skill in the art, employed concrete ointment base or emulsifiable paste matrix will provide the substrate that the best is passed medicine.As other carrier or solvent, ointment base should be inertia, stable, nonirritant and non-sensitization.

[0251] different with conventional peptide formulations, the present invention contains the amino acid whose peptide of D type even can orally give, and need not to protect proteolysis to avoid gastric acid etc.Yet, in certain embodiments, can strengthen sending of peptide by using the protectiveness excipient.This is normally by making its acid resistance and anti-enzyme hydrolysis or realize in the suitable resistance carrier (for example liposome) by polypeptide is packaged in polypeptide and compositions being compound.The method that is used for the protection polypeptide of oral delivery is (referring to for example United States Patent (USP) 5,391,377, it has been introduced and has been used for the treatment of the lipid composition that drug oral is sent) well-known in the art.

[0252] the serum half life that prolongs, can " be packed " system held with slow release protein.This slow-released system is well known to those skilled in the art.In a preferred embodiment, ProLease biological degradability microsphere delivery system (Tracy (1998) Biotechnol.Prog.14:108 that is used for protein and peptide; Johnson etc. (1996) Nature Med.2:795; Herbert etc. (1998), Pharmaceut.Res.15,357), be a kind of dry powder of forming by the biological degradability polymerizing microballoons, this microsphere contains activating agent at polymer backbone, the dry powder blend that contains or do not contain other activating agent can be made dry preparation.

[0253] ProLease microsphere manufacturing process is accurately designed, when keeping the activating agent integrity, to reach high encapsulation efficiency.This technology is made up of following steps: (i) by spraying freeze-dried drug solution and stable excipient, by powder (bulk) preparation freeze-dried drug granule, (ii) prepare the drug-polymer suspension, subsequently by supersound process or homogenate to reduce diameter of aspirin particle, (iii) by being sprayed in the liquid nitrogen, the drug-polymer microsphere that obtains freezing, (iv) polymer solvent is used alcohol extraction and (is v) filtered and vacuum drying obtains final power-product.Gained dry powder contains the activating agent of solid form, and it is dispersed in the porous polymer particles uniformly and stably.The polymer poly lactic acid-ethanol copolymer (PLG) that this technology is the most frequently used, be biocompatibility be again biodegradable.

[0254] seals and under low temperature (for example-40 ℃), to finish.When water did not exist during sealing, it is solid-state that protein keeps, and therefore the inductive protein conformation activeness of water minimized, and prevented to comprise the protein degradation reaction of water as reactant, avoided protein that the organic-water termination of degeneration may take place.Preferable methods adopts the undissolved solvent of most protein, therefore obtains high encapsulation efficiency (for example＞95%).

[0255] in another embodiment, one or more components in the solution can be used as " concentrate " and provide, and for example existing hold-up vessel (for example predetermined) with existing dilution is perhaps existing with the solubility capsule that now is added into the scale volume.

[0256] above-mentioned dosage form and medication are exemplary rather than nonrestrictive.Should be understood that, use the instruction that this paper provided, can easily design other suitable dosage form and administering mode.

B) based on the dosage form of lipid

[0257] in certain embodiments, activating agent of the present invention and one or more lipid drug combinations.Lipid can be mixed with the transhipment/absorption of excipient with protection and/or raising activating agent, and perhaps they can give separately.

[0258] under the situation that is not subjected to the particular theory constraint, the present invention finds that giving (for example orally give) some phospholipid can significantly increase the HDL/LDL ratio.In addition, we think that the phospholipid of some moderate-length is transported with the method that is different from common lipid transfer.Therefore, the phospholipid and the activating agent of the present invention that give some moderate-length jointly can provide many advantages: the protection activating agent is avoided digestion or hydrolysis, improves to absorb, and improves the HDL/LDL ratio.

[0259] lipid can form the liposome of sealing activating agent of the present invention and/or can mix with activating agent and/or can with the activating agent covalent coupling.The preparation method of liposome and seal reagent and be well known to those skilled in the art (referring to for example Martin and Papahadjopoulos (1982) J.Biol.Chem.257:286-288; Papahadjopoulos etc. (1991) Proc.Natl.Acad.Sci.USA, 88:11460-11464; Huang etc. (1992) Cancer Res.52:6774-6781; Lasic etc. (1992) FEBS Lett.312:255-258 etc.).

[0260] the fatty acid scope that is used for the preferred phospholipid of these methods at about 4 carbon atoms of sn-1 and sn-2 position to about 24 carbon atoms.In certain preferred aspects, fatty acid is saturated.In other embodiment preferred, fatty acid can be undersaturated.Various preferred fatty acids see Table 19.

[0261] table 19. is at the preferred fatty acid of the preferred phospholipid that is used for active agent delivery described herein in sn-1 and/or sn-2 position

Carbon number	Adopted name	The IUPAC title
			3:0 4:0 5:0 6:0 7:0 8:0 9:0 10:0 11:0 12:0 13:0 14:0 15:0 16:0 17:0 18:0 19:0 20:0 21:0 22:0 23:0 24:0 14:1 14:1 16:1 16:1	( Propionoyl ) ( Butanoyl ) ( Pentanoyl ) ( Caproyl ) ( Heptanoyl ) ( Capryloyl ) ( Nonanoyl ) ( Capryl ) ( Undcanoyl ) ( Lauroyl ) ( Tridecanoyl ) ( Myristoyl ) ( Pentadecanoyl ) ( Palmitoyl ) ( Heptadecanoyl ) ( Stearoyl ) ( Nonadecanoyl ) ( Arachidoyl ) ( Heniecosanoyl ) ( Behenoyl ) ( Trucisanoyl ) ( Lignoceroyl ) 9- ( Myristoleoyl ) ( 9- ) Myristelaidoyl ( 9- ) ( Palmitoleoyl ) ( 9- ) Palmitelaidoyl ( 9- )	( Trianoic ) ( Tetranoic ) ( Pentanoic ) ( Hexanoic ) ( Heptanoic ) ( Octanoic ) ( Nonanoic ) ( Decanoic ) ( Undecanoic ) ( Dodecanoic ) ( TrideGanoic ) ( Tetradecanoic ) ( Pentadecanoic ) ( Hexadecanoic ) ( Heptadecanoic ) ( Octadecanoic ) ( Nonadecanoic ) ( Eicosanoic ) ( Heniecosanoic ) ( Docosanoic ) ( Trocosanoic ) ( Tetracosanoic )

These locational fatty acids can be identical or different.Particularly preferred phospholipid has phosphocholine on the sn-3 position.

C) the special medicine/device of passing

1. bracket for eluting medicament (Drug-eluting stent)

[0262] (for example accounting for the 20-50% of these operations) takes place with very high ratio in restenosis (periphery of expansion or coronary vasodilator are closed again after narrow before), and depends on many clinical and form variablees.Restenosis can begin in the near future at angioplasty, but stops when finishing in about 6 months usually.

[0263] developed the state-of-the-art technology of tackling endovascular stent restenosis problem.Support is the crown and peripheral blood vessel persistency usual means when transplanting (expansion).The purpose of these supports provides chronicity " skeleton (scaffolding) " for ill (narrow) blood vessel or supports.See that theoretically if blood vessel is supported internally, it will can closure or restenosis.

[0264] known support Design includes but not limited to monofilament lines disc carrier (monofilament wire coil stent) (referring to for example United States Patent (USP) 4,969,458); Weld metal cage (welded metal cage) is (referring to for example United States Patent (USP) 4,733,665 and 4,776,337), have around around the thin-wall metal cylinder (thin-walled metalcylinder) of formed axial slits (referring to for example United States Patent (USP) 4,733,665,4,739,762,4,776,337 etc.).The known material that is used to make support includes but not limited to polymer, organic fiber and biocompatibility metal (for example rustless steel, gold, silver, tantalum, titanium) and marmem (for example nitinol).

[0265] in order further to prevent restenosis, support can be with one or more medicine parcel and/or infiltration, for example at the controlled release form that suppresses the relevant restenosis of cell proliferation.These " medicament elution " supports that great majority are commonly used are designed to sends various cancer drugs (cytotoxin).

[0266] in any case, since activating agent described herein in the reaction that reduces inflammation, reduce and/or remove the activity of lipid oxide and/or other oxidation intermediates, inhibition macrophage chemotactic activity etc., so be very suitable for preventing restenosis.Therefore, in certain embodiments, the present invention includes and have one or more activating agents described herein and be coated on the surface and/or keep the lacuna of rack surface or the support in the microcavity crack.

[0267] in certain embodiments, activating agent is included in the biocompatibility skeleton (the biological example compatible polymer is urethanes, siloxanes etc. for example).Suitable biocompatible materials is referring to for example United States Patent (USP) publication: 20050084515,200500791991,20050070996 etc.In different embodiments, polymer includes but not limited to siloxanes-urethane copolymers, polyurethane, phenoxy group polymer, ethylene vinyl acetate, polycaprolactone, polylactic-co-glycolic acid, polyactide, polysulfones, elastin laminin, fibrin, collagen protein, chondroitin sulfate, biocompatible polymer, biostable polymer, biodegradable polymer.

[0268] therefore, in certain embodiments, the invention provides the support that is used for delivering drugs in the body tube chamber.Support generally includes Support frame, is included in wherein formed a plurality of storages storehouse in this framework.The polymer that the storage storehouse generally includes activating agent and/or contains activating agent is positioned at the storage storehouse and/or is coated on rack surface.In different embodiments, support is metallic substrates or polymeric substrates.Some preferred timbering material includes but not limited to rustless steel, nitinol, tantalum, MP35N alloy, platinum, titanium, suitable biocompatible alloy, suitable biocompatible polymer and/or their combination.

[0269] in different embodiments, support comprises aperture (for example storing the storehouse), and aperture can comprise micropore (for example the about 10 μ m of diameter range are to about 50 μ m, and preferred about 20 μ m are following).In different embodiments, the about 10 μ m of the depth bounds of micropore are to about 50 μ m.In different embodiments, micropore spreads all on the entire bracket framework, and Support frame respectively has a perforate at the inner surface of support and the outer surface of support.In certain embodiments, support can be chosen wantonly and comprise the cover layer that is configured on the Support frame inner surface, and cover layer wraps up at least a portion in whole hole, and the speed that discharges from the Support frame inner surface polymer for the control activating agent provides barrier characteristics.In different embodiments, the storage storehouse comprises along the passage of Support frame outer surface.Support can be chosen wantonly has multiple layer polymer, and wherein the polymer of different layers carries different activating agents and/or other medicines.

[0270] in certain embodiments, support comprises: the adhesion layer between Support frame and polymer.Suitable adhesion layer includes but not limited to polyurethane, phenoxy group polymer, polylactic-co-glycolic acid, polyactide, polysulfones, polycaprolactone, adhesion promoter and/or their combination.

[0271] except that support, activating agent can wrap by or be included in almost any implantable medical device, be used for outer position of implantable intravascular and/or internal blood vessel position.

[0272] the present invention also provides the method for making the drug-polymer support.This method comprises provides Support frame; On Support frame, cut out a plurality of storages storehouse (for example adopting superlaser); One or more activating agents and/or pharmaceutical polymer are applied at least one storage storehouse; With the pharmaceutical polymer drying; Polymeric layer is applied in the dry drug polymer; With the polymer drying.Can apply activating agent and/or polymer by any easy method, include but not limited to spray, flood, smear, brush and disperse.

[0273] the present invention also is provided for treating angiopathy and/or is the disease of feature and/or with the method for the disease that forms feature of oxidation activity intermediate with the inflammatory reaction.This method generally includes aforesaid support or other implantable device are implanted (for example in the body tube chamber), and at least a activating agent is discharged from least one surface of implant.

2. flood graft and implant

[0274] blood vessel graft can be divided into biograft or synthetic graft.Biograft has two kinds of common type.Autograft is a graft of taking from another position of patient body.This up to now the most frequently used graft is a long saphenous vein in the peripheral blood vessel operation.This can use in position, and valve destroys by operation with cutting type valvulotome in the tube chamber.

[0275] or, can clip vein and make it the upset, but this produces difference usually between tremulous pulse and venous anastomosis size.In the thoracic operation, the purposes of IMA is another example of autograft in the coronary bypass-forming operation.Allograft is a graft of taking from same species different animals.Seldom use the outside umbilical vein that is supported, but this also is an example of graft.

[0276] synthetic graft is the most generally made by Dacron or polytetrafluoroethylene (PTFE).The Dacron graft is through being usually used in the operation of operation on aorta and aorta iliac artery.Below the inguinal ligament, the result of all synthetic grafts is not so good as the ideal as a result that use vein transplantation thing is obtained.Owing to be not that total energy obtains suitable vein, use PTFE in this case usually.It can be united as composite graft with vein and uses.Combination that can be by vein segment to promote the long-term opening of graft, reduces far-end anastomosis neointimal hyperplasia as Millar Cuff or Taylor Patch.

[0277] most common complication relevant with using blood vessel graft comprises the true and false property aneurysm, distal embolization of graft obturation, graft infection, anastomotic position and near the erosion (for example AEF) of structure.There are many and inflammatory reaction, macrophage migration to transplantation site and/or reactive oxygen intermediate (for example lipid oxide) to form relevant in these diseases.In order to reduce these complication, graft (synthetic graft or biograft) can be soaked or the bag quilt with one or more activating agents described herein.

[0278] in addition, it is generally acknowledged that other implantable tissue or material can be equally with one or more activating agent dipping of the present invention or bag quilts.For example, in certain embodiments, the present invention includes and use impregnated suture so that inflammation and/or infection and/or tissue rejection minimize.

3. subcutaneous skeleton

[0279] in certain embodiments, one or more activating agents described herein are used for implantable (for example subcutaneous) skeleton or unite with other curative as herein described and to be used for implantable (for example subcutaneous) skeleton separately.

[0280] subject matter of standard drug dosage is to pass medicine usually to cause that medicine breaks rapidly when administration, the loss fast in the body that thereupon is medicine.Most drug side effect occurs in medicine and breaks when being discharged in the blood flow mutually.Secondly, medicine has the time of treatment level very short in blood flow, is consumed and disposes when of short duration breaking mostly.

[0281] is embedded in the medicine (activating agent for example described herein) that is used for slow release in the various framework materials and provides solution for these problems.The medicine of institute's embedding (for example medicine in polymer microbeads or the polymer disk) has some advantages.At first, most systems makes and therefore causes medicament slow release and quantitatively give low-level medicine in the body continuously.This has prevented usually with the routine injection or based on the relevant side effect of the high breakage level of pill medicine.Secondly, discharge owing to these polymer can be formed in a few hours to several months, so the treatment phase of medicine significantly strengthens.Usually by the same polymeric composition of different proportion is mixed, can prepare the polymer of different degradation rates, tangible mobility is provided, this depends on used medicine.For the people (for example elder) who keeps routine dose to go wrong, drug release over a long time is useful, but makes usage be able to improved facility, and everyone can both be benefited.Most polymers can be prepared into as time goes by degradation in vivo and be eliminated, and therefore will can not keep in vivo in treatment at interval.

[0282] another advantage of passing medicine based on polymer be polymer usually can make can't be as protein, peptide and other macromole of medicine stable or solubilising.At last, many drug/polymer mixture directly can be delivered to disease sites, make the selectively targeted desired area of medicine and do not lose " first cross " effect of medicine.This can be effective to the brain treatment certainly, because brain normally makes medicine can not pass blood/brain barrier.

[0283] many implantable skeletons (slow release) system is known to those skilled in the art, can easily be applicable to one or more activating agents as herein described.Suitable slow-released system includes but not limited to Re-Gel , SQ2Gel  and the Oligosphere  that MacroMed company produces, ProLease  and Medisorb  that Alkermes company produces, Paclimer  and Gliadel  Wafer that Guilfordpharmaceuticals company produces, the Duros implant that Alza company produces, the audition bioSpheres that Point Biomedical company produces, the Intelsite capsule that Scintipharma company produces, or the like.

4. other " special-purpose delivery system "

[0284] other " special use " delivery system includes but not limited to: the saturating mucosa (OTS of system in oral cavity of the oral spray based on lipid of GenerexBiotechnology company exploitation (it allows medicine to absorb by oral mucosa), the exploitation of Anesta company ^TM), the sucked dry powder doses of InhaleTherapeutics company exploitation and PulmoSpheres technology, the AERx  pulmonary delivery system of Aradigm company exploitation, the AIR mechanism of Alkermes exploitation, or the like.

[0285] another kind of delivering method by the exploitation of Alkermes company is a kind ofly to use the system as object with gerontal patient and pediatric patients (these two kinds of patients take pill and usually have any problem), often be called as medicine inhale the drink technology (Drug Sipping Technology, DST).Medicine pack into one with in the device of suction pipe for the suction drink, and its two ends respectively have a filter to prevent that medicine from spilling.The patient is only as long as drink limpid liquid (water, fruit juice, carbonated water) by suction pipe.The medicine that is dissolved in liquid is in fact by in patient's suction nozzle and swallow.Filter rises to the suction pipe top when all medicines are sucked.The advantage of this method is easy to use, and liquid has usually been covered the disagreeable taste of medicine, and medicine dissolves in advance, can more effectively be absorbed.

[0286] is noted that these usages and delivery system are exemplary rather than nonrestrictive.Use instruction provided herein, other usage and delivery system are known to those skilled in the art.

VI. other pharmacologically active agent

The activating agent of combination

[0287] in different embodiments, the coupling of two or more activating agents is included in the treatment of various pathology/indications described herein.The coupling of activating agent can change pharmacologically active, bioavailability etc.

[0288] for instance, be noted that, D-4F and preceding β HDL and HDL associate fast, from circulation, remove fast then (behind oral administration, can not detect basically in 6 hours), D-[113-122] apoJ then slowly associates with preceding β HDL, lower with the HDL associating intensity, but keep and these HDL association partly at least 36 hours.FREL and HDL and only associate with HDL, but in the time more much longer, in HDL, still can detect (that is to say the administration of mice single oral after 48 hours in HDL, still can detect) than D-4F.In certain embodiments, therefore the present invention comprises for example combination of these three kinds of peptides, with the minimizing consumption, thereby reduces producing cost, and/or makes optimizations such as dosage, treatment plan.In certain embodiments, the combination of activating agent described herein can be to give jointly and/or be added in to form independent pharmaceutical preparation together.In certain embodiments, various activating agents can combine (for example passing through hydrogen bonded) formation than the effective activating agent complex of parent drug.

The purposes of other pharmacologically active material

[0289] other pharmacologically active material (being medicine) can with one or more activating agent drug combinations described herein.In certain embodiments, these medicines include but not limited to reduce the medicine of atherosclerosis generation and/or its complication risk.These medicines include but not limited to β blocade, β blocade and thiazide diuretic coupling, inhibin, aspirin, ace inhibitor, ace acceptor inhibitor (ARB) etc.

[0290] we find, low dosage activating agent (for example D-4F of low dosage) (1 μ g/ml) is joined in the drinking water of apoE nude mouse and can significantly not improve the HDL function (referring to for example related application USSN 10/423 of application on April 25th, 2003 in 24 hours, 830, the content of this application is attached to herein by reference).In addition, 0.05mg/ml atorvastatin or pravastatin are joined separately in the apoE nude mouse drinking water and can not improve the HDL function in 24 hours.Yet if 1 μ g/ml D-4F is joined drinking water with the 0.05mg/ml atorvastatin or with pravastatin, the HDL function significantly improves.In fact, urging scorching apoE nude mouse HDL becomes and the same antiinflammatories of 350 μ g/ml normal person HDL (h HDL) (referring to for example related application USSN10/423,830).

[0291] therefore, itself was to the not effect of HDL function, if give jointly then bring into play potentiation when D-4F or inhibin gave separately.If give apo E nude mouse together with D-4F and inhibin, in human artery parietal cell coculture, preventing that aspect the inductive inflammatory reaction of effect of HPODE oxidation PAPC, it is the same effective with the normal person HDL of 350 μ g/ml HDL-cholesterol that the short scorching HDL of 50 μ g/ml HDL-cholesterol becomes.

[0292] therefore, in certain embodiments, the invention provides and improve the active method of inhibin.This method generally includes by methods described herein one or more activating agents described herein and one or more inhibin drug combinations.This activating agent reaches potentiation between inhibin and medicine, to improve atherosclerotic one or more symptoms.At this on the one hand, the dosage medication that inhibin can be obviously lower, thus avoid various and the relevant harmful side effect (for example amyotrophy) of high dose inhibin use, and/or the antiinflammatory performance of inhibin significantly improves when giving with any dosage.

[0293] suitable inhibin includes but not limited to pravastatin (Provastain (Pravachol)/Bristol-Myers Squibb company), simvastatin (simvastatin (Zocor)/Merck company), lovastatin (Mevacor/Merck company) etc.

[0294] in different embodiments, activating agent described herein and one or more β blocade drug combinations.Suitable β blocade includes but not limited to heart selectivity (selectivity β 1 blocade), for example acebutolol (Sectral ^TM), atenolol (Tenormin ^TM), betaxolol (Kerlone ^TM), bisoprolol (Zebeta ^TM), metoprolol (Lopressor ^TM) etc.Suitable non-selective blocade (blocking β 1 and β 2 on an equal basis) includes but not limited to carteolol (Cartrol ^TM), nadolol (Corgard ^TM), penbutolol (Levatol ^TM), pindolol (Visken ^TM), Propranolol (Inderal ^TM), timolol (Blockadren ^TM), labetalol (Normodyne ^TM, Trandate ^TM) etc.

[0295] suitable β blocade thiazide diuretic combination includes but not limited to LopressorHCT, ZIAC, Tenoretic (Tenoretic), nadolol and bendroflumethiazide tablet (Corzide), Timolide, Inderal LA 40/25, Inderide (Inderide), Normozide etc.

[0296] suitable ace inhibitor comprises but is not limited to the captopril (Capoten that produces of Squibb company for example ^TM), the benazepril (Lotensin that produces of Novartis company for example ^TM), the enalapril (Vasotec that produces of Merck company for example ^TM), the fosinopril (Monopril that produces of Bristol-Myers company for example ^TM), the lisinopril (Prinivil that produces of Merck company for example ^TMOr the Zestril of Astra-Zeneca company production ^TM), the quinapril (Accupril that produces of Parke-Davis company for example ^TM), the ramipril (Altace that produces of HoechstMarion Roussel, King Pharmaceuticals company for example ^TM), imidapril, the perindopril elbumin (Aceon that produces of Rhone-Polenc Rorer company for example ^TM), the trandolapril (Mavik that produces of Knoll Pharmaceutical company for example ^TM) etc.Proper A RBS (Ace beta blocker) includes but not limited to the losartan (Cozaar that produces of Merck company for example ^TM), the irbesartan (Avapro that produces of Sanofi company for example ^TM), the Candesartan (Atacand that produces of Astra Merck company for example ^TM), the valsartan (Diovan that produces of Novartis company for example ^TM) etc.

[0297] in different embodiment, with one or more activating agents described herein and one or more medication combined medications given below.

[0298] for example; in certain embodiments, one or more activating agents and following activating agent drug combination: cetp (CETP) inhibitor (torcetrapib for example; JTT-705.CP-529414) and/or acyl-CoA: cholesterol O-acyltransferase (ACAT) inhibitor (avasimibe (CI-1011) for example; CP113818; F-1394 etc.); and/or immunomodulator (FTY720 (sphingosine-1-phosphate receptor agonist) for example; Thalomid (Thalidomide); according to Drymotaenium miyoshianum (Mak.) Mak. (azathioprine); Ke Pasong (Copaxone) (acetic acid glatiramer); Certican  (everolimus); Neoral  (cyclosporin) etc.); and/or two peptidyls-peptidase-4 (DPP4) inhibitor (for example 1-[[[2-[(5-cyano group-2-pyridine radicals) amino] ethyl] amino] acetyl group-2-pyrrolidine formonitrile HCN]; also can be) referring to United States Patent (USP) publication 2005-0070530; and/or calcium channel blocker (Adalat for example; Adalat CC; the verapamil preparation; slow release verapamil preparation; cardene; diltiazem hydrochloride ; diltiazem hydrochloride  CD; slow release diltiazem hydrochloride ; hydrochloric acid ground two sulfur  slow releasing capsulees; isradipine; isoptin; the slow release isoptin; nimotop; Norvasc; Plendil; Procardia; Procardia XL; vascor; the verapamil slow releasing capsule); and/or for for example α; γ; the peroxisome proliferation-activated receptors of δ receptor (PPAR) agonist (Azelaoyl PAF for example; 2-bromine hexadecanoic acid; Ciglitizone; clofibrate; 15-deoxidation-δ ^12,14-prostaglandin J ₂, fenofibrate, Fmoc-Leu-OH, GW1929, GW7647,8 (S)-hydroxyl-(5Z, 9E, 11Z, 14Z)-arachidonic acid (8 (S)-HETE), leukotriene B ₄, LY-171,883 (tomelukasts), prostaglandin A ₂, prostaglandin J ₂, TTA (TTA), troglitazone (CS-045), WY-14643 (pirinixic acid)) etc.

[0299] in certain embodiments; with one or more activating agents and following medication combined medication: the special class (fibrate) of shellfish (clofibrate (clofibrate (atromid)) for example; gemfibrozil (gemfibrozil (lopid)); fenofibrate (fenofibrate tablet (tricor)) etc.); bile acid chelating agent (colestyramine for example; colestipol etc.); cholesterol absorption blocade (for example ezetimibe (Zetia) etc.); Vytorin ((ezetimibe/simvastatin combination); and/or steroid; warfarin; and/or aspirin; and/or Bcr-Ab1 inhibitor/antagonist (Gleevec (imatinib mesylate) for example; AMN107; STI571 (CGP57148B); ON 012380; PLX225 etc.); and/or renin angiotensin approach blocade (losartan (Cozaar ) for example; valsartan (Diovan ); irbesartan (Avapro ); Candesartan (Atacand ) etc.); and/or angiotensin ii receptor antagonist (losartan (losartan (Cozaar)) for example; valsartan (DAIWEN (Diovan)); irbesartan (Avapro); Candesartan (Atacand) and telmisartan (Micardis (Micardis)) etc.); and/or pkc inhibitor (Calphostin C for example; Chelerythrine chloride; two-3,5-diisopropyl copper salicylate; ebselen; EGF receptor (people) is (N-myristoylation) (651-658); G  6976; two hydrochloric acid H-7; 1-O-cetyl-2-O-methyl-rac-glycerol; cetyl-phosphocholine (C _16:0); Miltefosine, hypericin, melittin (natural), melittin (synthesizing), hydrochloric acid ML-7, hydrochloric acid ML-09, hydrochloric acid palmityl-DL-carnitine, Protein kinase C (19-31), Protein kinase C (19-36), Quercetin dihydrate, Quercetin dihydrate, D-erythro-sphingol (isolating), D-erythro-sphingol (synthesizing), sphingol, N, N-dimethyl-D-erythro-sphingol, dihydro-D-erythro-sphingol, chlorination N, N-dimethyl-D-erythro-sphingol, N, N, N-trimethyl-staurosporin, bisindole maleimide I, G-6203 etc.).

[0300] in certain embodiments, with one or more activating agents and following composition drug combination: (ApoAI milano for example is referring to for example United States Patent (USP) publication: 20050004082,20040224011,20040198662,20040181034,20040122091,20040082548,20040029807,20030149094,20030125559,20030109442,20030065195,20030008827 and 20020071862 for Apo AI, Apo A-I derivant and/or agonist; United States Patent (USP) 6,831,105,6,790,953,6,773,719,6,713,507,6,703,422,6,699,910,6,680,203,6,673,780,6,646,170,6,617,134,6,559,284,6,506,879,6,506,799,6,459,003,6,423,830,6,410,802,6,376,464,6,367,479,6,329,341,6,287,590,6,090,921,5,990,081 etc.), renin inhibitor (for example SPP630 and SPP635, SPP100, aliskiren etc.), and/or MR antagonist (spironolactone for example, aldosterone glucosiduronic acid etc.), and/or aldosterone synthase inhibitors, and/or alpha-adrenergic aceptor antagonist (Aldomet  (methyldopa) for example, Cardnra  (doxazosin), Catapres ; Catapres-TTS ; DuraclonTM (clonidine); Dibenzyline  (phenoxybenzamine); Hylorel  (guanadrel); Hytrin  (terazosin); Minipress  (prazosin); Tenex  (guanfacine); guanabenz; phentolamine; reserpine etc.); and/or liver X receptor (LXR) agonist (T0901317 for example; GW3965; ATI-829; acetyl group-podocarpic acid dimer (acetyl-podocarpic dimer; APD) etc.); and/or farnesol X receptor (FXR) agonist (GW4064 for example; 6 α-ethyl-chenodeoxy cholic acid (6-ECDCA); T0901317 etc.); and/or activator of plasminogen-1 (PAI-1) inhibitor is (referring to for example based on the PAI-1 inhibitor of oxime; other sees United States Patent (USP) 5; 639,726 etc.); and/or low molecular weight heparin; and/or AGE inhibitor/clastogen (benfotiamine for example; aminoguanidine; pyridoxamine; tenilsetam; pimagedine etc.) and/or adp receptor blocade (clopidogrel for example; AZD6140 etc.); and/or ABCA1 agonist; and/or removing receptor B1 agonist; and/or adiponectin receptor agonist or adiponectin inducer; and/or stearyl-coenzyme A desaturase I (SCD1) inhibitor; and/or cholesterol synthetic inhibitor (non-inhibin class); and/or Diacrylglycerol acyl transferase I (DGAT1) inhibitor; and/or acetyl-CoA carboxylase inhibitor 2; and/or LP-PLA2 inhibitor; and/or GLP-1; and/or glucokinase activating agents; and/or CB-1 agonist; and/or antithrombotic drug/coagulant; and/or factor Xa inhibitor; and/or GPIIb/IIIa inhibitor; and/or factor VIIa inhibitors; and/or tissue factor inhibitor; and/or anti-inflammatory drug; and/or probucol and derivant (for example AGI-1067 etc.); and/or CCR2 antagonist; and/or CX3CR1 antagonist; and/or IL-1 antagonist; and/or nitrate and NO donor; and/or phosphodiesterase inhibitor etc.

IX. the medicine box that is used for the treatment of one or more indications

[0301] in another embodiment, the invention provides to be used to improve atherosclerotic one or more symptoms or to be used for prophylactic treatment and curee of atherosclerosis risk (human or animal) and/or treatment are arranged or prevent the medicine box of one or more diseases described herein.Medicine box preferably includes the container that one or more activating agents described herein are housed.Activating agent can unit dose formulations (for example suppository, tablet, capsule tablet, patch etc.) provide and/or can choose wantonly and one or more pharmaceutically acceptable mixed with excipients.

[0302] medicine box also can be chosen wantonly and comprise that one or more are used for the treatment of the other medicines of target disease/pathology.These medicines include but not limited to for example aforesaid β blocade, vasodilator, aspirin, inhibin, ace inhibitor or ace acceptor inhibitor (ARB) etc.

[0303] in addition, medicine box is optional comprises label and/or for implementing the furnish an explanation operation instructions of (being scheme) of the inventive method or the present invention's " curative " or " preventive drug " usage.Indicate on the preferred operation instructions and use one or more activating agents of the present invention to alleviate one or more symptoms of atherosclerosis (other pathology perhaps as herein described) and/or prevent the outbreak of one or more these symptoms of atherosclerosis (other pathology perhaps as herein described) risk individuality or the usage that increases the weight of.Also can choose wantonly on the operation instructions and indicate preferred consumption/therapeutic scheme, antagonism indication etc.

[0304] though operation instructions generally include written or printed material, is not limited thereto.The present invention also comprises any medium that can store these directions for uses and pass to the terminal use.These media include but not limited to electronic storage medium (for example disk, tape, cassette tape (dish), chip), optical medium (for example CD ROM) etc.Can comprise in these media and provide these to use the network address of the Internet of information material.

Embodiment

[0305] the following examples are used to illustrate the present invention, but not and be restriction to claimed invention.

Embodiment 1

Use ApoJ related peptides mediation atherosclerosis shape

Suppress the inductive monocyte chemotactic activity of LDL

[0306] Fig. 1 is illustrated in when hatching altogether, for the inductive monocyte chemotactic activity of vitro inhibition LDL, D-4F (Anantharamaiah etc. (2002) (2002) Circulation, effect 105:290-292) and the apoJ peptide (D-J336, the Ac-L-L-E-Q-L-N-E-Q-F-N-W-V-S-R-L-A-N-L-T-Q-G-E-NH that prepare with D aminoacid ₂, SEQ ID NO:1177)) effect comparison.The human aorta endotheliocyte only with culture medium (add), with contrast people LDL (200 μ g albumen/ml) or contrast people LDL+ contrast people HDL (350 μ g HDL albumen/ml) hatch.The D-J336 or the D-4F of normal concentration scope are added contrast people LDL (200 μ g albumen/ml) join in other hole.After the night incubation, measure the monocyte chemotactic activity of supernatant.As shown in Figure 1, suppress to induce the external concentration ratio D-4F peptide desired concn of the active apoJ variation of monocyte chemotactic peptide low 10-25 times by the LDL due to the human artery parietal cell.

Press down the inductive monocyte chemotactic of LDL is active with D-J336 pretreatment arterial wall cell System

When [0307] Fig. 2 is illustrated in preincubate, for suppressing the inductive monocyte chemotactic activity of LDL, the comparison of the effect of D-4F and D-J336 effect.The human aorta endotheliocyte was with D-J336 or D-4F preincubate 6 hours, and DJ336 concentration is 4 μ g/ml, 2 μ g/ml and 1 μ g/ml, and D-4F concentration is 100 μ g/ml, 50 μ g/ml, 25 μ g/ml and 12.5 μ g/ml.Then, culture after washing, only with culture medium (add) or with contrast people LDL (200 μ g albumen/ml) or with contrast people LDL+ contrast people HDL (350 μ g HDL albumen/ml) hatch as experiment contrast.Add contrast people LDL in pretreated each hole of peptide, concentration is 200 μ g albumen/ml.After the night incubation, measure the monocyte chemotactic activity of supernatant.

[0308] as shown in Figure 2, aspect the LDL oxidation due to the arterial wall cell, the effect of ApoJ variation peptide wants high 10-25 doubly in vitro inhibition.

Apo J peptide mimics is to the effect of HDL protective capability in the ldl receptor nude mouse

[0309] join in ldl receptor nude mouse (4 s'/group) the drinking water with D-4F (be called for short F) or by the apo J peptide (D-J336 is called for short J) of D aminoacid preparation, concentration is 0.25mg/ml or 0.5mg/ml drinking water.After 24 hours or 48 hours, collect mouse blood, isolate its HDL, measure it and prevent the active ability of the inductive monocyte chemotactic of LDL.Experiment contrast comprises the culture hole that contains following composition: do not add lipoprotein (add) or only add contrast people LDL and (be called for short LDL, 200 μ g cholesterol/ml) or add contrast LDL+ contrast people HDL (abbreviation+HDL, 350 μ g HDL cholesterol).For measuring mice HDL, will contrast LDL and join in the arterial wall cell culture with mice HDL (+F HDL or+J HDL).Add mice HDL (100 μ g cholesterol/ml) respectively.Behind the D-4F mice HDL or D-J336 mice HDL processing with 100 μ g/ml, suppress the same effective from inducing arterial wall cell to produce the active contrast of monocyte chemotactic LDL with 350 μ g/ml contrast people HDL.With respect to D-4F, the reason of difference may be relevant with peptide dissolubility in water between the required D-J336 peptide relative dosage of inside and outside, and we think if reach equal dissolubility when measuring, then the D-J peptide in vivo will with external the same more effective.

The apo E nude mouse HDL that gives oral peptide prevents that the inductive monocyte chemotactic of LDL is alive The property

[0310] Fig. 4 represents the effect to the HDL protective capability of oral apoA-1 peptide mimics and apoJ peptide.By 50 μ g/ml, 30 μ g/ml, 20 μ g/ml, 10 μ g/ml, 5 μ g/ml drinking waters, perhaps supply with ApoE nude mouse (4/group) D-4F (being called for short F) or apoJ peptide (being called for short J) respectively by 50 μ g/ml, 30 μ g/ml or 20 μ g/ml drinking waters.After 24 hours, gather blood, blood plasma FPLC fractionated; merge respectively and contain the part of LDL (for Mus LDL; be called for short mLDL) and contain the part (being called for short mHDL) of HDL, by the inductive monocyte chemotactic activity of mensuration LDL, measure HDL protective capability at the LDL oxidation.For experiment contrast, do not add lipoprotein (add) in the culture hole, only add mLDL (200 μ g cholesterol/ml) or add mLDL+ standard normal person HDL and (be called for short Cont.h HDL, 350 μ g HDL cholesterol/ml).

[0311] for measuring Mus HDL, with mLDL with Mus HDL (+F mHDL or+JmHDL) join in the arterial wall cell culture.The HDL that does not add any peptide gained in the mice drinking water is called no peptide mHDL.Use Mus HDL by 100 μ g cholesterol/ml.After adding the D-4F Mus HDL or D-J336 Mus HDL of 100 μ g/ml, the same effective with 350 μ g/ml normal person HDL.As shown in Figure 4, in joining drinking water after, in apo E nude mouse, improve aspect the HDL protective capability, the D-J peptide is the same with D-4F effective.

The LDL that obtains from the apoE nude mouse that gives oral peptide induces the monocyte chemotactic activity Ability

[0312] Fig. 5 represents the effect to the LDL oxidation sensitive of oral apo A-1 peptide mimics and apoJ peptide.Press 50 μ g/ml, 30 μ g/ml, 20 μ g/ml, 10 μ g/ml, 5 μ g/ml drinking waters or press 50 μ g/ml, 30 μ g/ml or 20 μ g/ml drinking waters, in drinking water, supply with ApoE nude mouse (4/group) D-4F (being called for short F) or apoJ peptide (, being called for short J) respectively by the D-J336 of D aminoacid preparation.After 24 hours, gather mouse blood, see Fig. 4, blood plasma FPLC fractionated merges the part (for Mus LDL, being called for short mLDL) that contains LDL, by measuring inductive monocyte chemotactic activity, measures the LDL oxidation sensitive.For experiment contrast, do not add lipoprotein (add) in the culture hole, only add mLDL (200 μ g cholesterol/ml) or add mLDL+ standard normal person HDL (being called for short Cont.h HDL, 350 μ gHDL cholesterol).

[0313] will derive from the Mus LDL (mLDL) that accepts D-4F (F mLDL) or accept apoJ peptide (J mLDL) mice, join in the arterial wall cell culture.Derive from the mice LDL that does not accept any peptide in the drinking water and be called as no peptide LDL.

[0314] as shown in Figure 5, when D-J336 joins in the drinking water, make, as inducing that the monocyte chemotactic activity measured from the effect of the anti-human artery parietal cell of the LDL of apo E nude mouse oxidation summary height than D-4F.

The HDL protection phospholipid that obtains from the apo E nude mouse that gives oral peptide is avoided oxidation and is kept away Exempt to induce the monocyte chemotactic activity

[0315] Fig. 6 represents the effect to the HDL protective capability of oral apoA-1 peptide mimics and apoJ peptide.Supply with ApoE nude mouse (4/group) D-4F (being called for short F) or apoJ peptide (, being called for short J) respectively by 50 μ g/ml, 30 μ g/ml, 20 μ g/ml, 10 μ g/ml, 5 μ g/ml drinking waters or by 50 μ g/ml, 30 μ g/ml or 20 μ g/ml drinking waters by the D-J336 of D aminoacid preparation.Blood sampling after 24 hours, blood plasma FPLC fractionated merges the part (being called for short mHDL) that contains HDL, by measuring inductive monocyte chemotactic activity, measures the protective capability of HDL at the PAPC oxidation.For experiment contrast, do not add lipoprotein (adding), adding 20 μ g/ml phospholipid PAPC+1.0 μ g/ml HPODE or PAPC+HPODE in the culture hole and add standard normal person HDL (350 μ g HDL cholesterol/ml, abbreviation+Cont.h HDL).

[0316], PAPC+HPODE is joined in the arterial wall cell culture with Mus HDL (+F mHDL or+J mHDL) in order to measure Mus HDL.Derive from the mice HDL that does not add any peptide in the drinking water and be called as " no peptide mHDL ".Use Mus HDL by 100 μ g cholesterol/ml.

[0317] data shown in Figure 6 show, in the time of in joining drinking water, D-J336 makes HDL suppress aspect oxidized dose of HPODE oxidation of phospholipid PAPC in human artery's wall is cultivated altogether, and is the same with D-4F effective, as producing that the monocyte chemotactic activity measured.

Oral apoA-1 peptide mimics and apoJ peptide are to the active effect of mice plasma paraoxonase

[0318] Fig. 7 represents that oral apoA-1 peptide mimics and apoJ peptide are to the active effect of mice plasma paraoxonase.By 50 μ g/ml, 10 μ g/ml, 5 μ g/ml or 0 μ g/ml drinking water or by 50 μ g/ml, 10 μ g/ml or 5 μ g/ml drinking waters, supply with ApoE nude mouse (4/group) D-4F (being called for short F) or apoJ peptide (, being called for short J) respectively by the D-J336 of D aminoacid preparation.Blood sampling after 24 hours, blood plasma is used to measure the PON1 activity.These data show, and are when D-J336 joins in the drinking water, aspect the paraoxonase activity of increase apo E nude mouse, the same with D-4F at least effective.

Embodiment 2

The oral G of Apo E deficient mice ^*Peptide increases the protective capability of HDL

The G of [0319] 4 month female apoE deficient mice (every group of n=4) with following aminoacid sequence ^*Peptide is handled: peptide 113-122=Ac-L V G R Q L E E F L-NH ₂(SEQ IDNO:9), peptide 336-357=Ac-L L E Q L N E Q F N W V S R L A N L T Q GE-NH ₂(SEQ ID NO:17) and peptide 377-390=Ac-P S G V T E V V V K L F DS-NH ₂(SEQ ID NO:19).

[0320] give every mice 200 μ g peptides with stomach tube.Obtain blood after 4 hours, separated plasma obtains lipoprotein, and HDL (25 μ g/ml) is at the protective capability of LDL (100 μ g/ml) oxidation in the mensuration human artery parietal cell culture.Data are seen Fig. 8.In the mice, this peptide provides significant HDL protective capability to mice.

[0321] in another experiment, 4 month female apoE deficient mices (every group of n=4) are handled with 11 with following sequence amino acid whose G* peptide 146-156: Ac-Q Q T H ML D V M Q D-NH ₂(SEQ ID NO:11).This peptide concentration is in accordance with regulations supplied with mice (referring to Fig. 9) in drinking water.Obtain blood after 18 hours, separated plasma obtains lipoprotein, measures in the human artery parietal cell culture, and (50 μ g cholesterol/ml) are at the protective capability of PAPC (25 μ g/ml)+HPODE (1.0 μ g/ml) oxidation for HDL.Experiment contrast comprise not interpolation, PAPC+HPODE and PAPC+HPODE add contrast HDL (be called for short+HDL).Data be the meansigma methods of the mononuclear cell numbers of migration in 9 high power fields in the culture (in triplicate)+/-SD.Significance level p＜0.05 with respect to water contrast (0 μ g/ml) represented in asterisk.

Embodiment 3

The solution phase chemistry synthetic method of peptide

[0322] in certain embodiments, solution is combined to chemical method and provides more economical synthetic method for peptide of the present invention.

[0323] before synthetic method of the present invention, use full solid phase synthesis chemical method to synthesize usually.Less than the solid phase synthesis of 9 amino acid peptides than more economically greater than the solid phase synthesis of 9 amino acid peptides.Since the physical solution that extends amino acid chain on the resin from, greater than the synthetic material heavy losses that cause of 9 amino acid whose peptides.Contain more economically, because the loss of extended chain is less relatively on the resin less than the solid phase synthesis of 9 amino acid whose peptides.

[0324] in certain embodiments, by with 18 aminoacid apoA-I simulating peptide, 4F (with other related peptides) synthetic from full solid phase synthesis or be transformed into whole soln and be combined to, perhaps be transformed into after respectively containing the solid phase synthesis of 6 amino acid whose 3 chains for example, the combination of these 3 chains of assembling in solution, thus solution is combined to and plays a role.This provides more cost effective overall synthetic.If peptide length is not 18 aminoacid, this method then also is easy to improve.For example, can be by behind 3 pentamers of solid phase synthesis, these 3 chains of assembling synthesize ten pentamers in solution.Can by behind 2 pentamers of solid phase synthesis and 1 tetramer in solution these chains of assembling synthesize 14 aggressiveness, or the like.

A) synthetic schemes catalog

Peptide D4F (Ac-D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-NH ₂The synthesis flow of (SEQID NO:5) sees Table 20.Synthesis flow and yield see Table 20.

[0325] the exemplary solution of table 20. is combined to flow process

Be used for the synthetic method of D4F
	Synthetic	Resin	Fmoc aminoacid		Coupling reagent	Resin final weight (g)		Rough peptide weight (g) yield (%)	Pure peptide weight (mg) yield (%)
The substep solid phase										Rink amide (1mmol) 1.8g	6 equivalents		HBTU/HOBT	4		2.0 86	500 25
	The substep solid phase	Rink amide (1mmol) 1.8g	2 equivalents		DIC/HOBT	3.9		2.0 86	450 22.5
Fragment coupling (6+6+6)										Rink amide (1mmol) 1.8g *			HBTU/HOBT	3.3		1.0 43	100 10
	D4F is segmental synthetic Fragment 1 on the rink amide resin (2HN-KFKEAF (SEQ ID NO:1178) (K and E are due cares)
26 residue substeps of fragment solid phase		Cl-TrT-resin (5mmol) 6.5g		6 equivalents	HBTU/HOBT			11	2.2 raw product protected 36
	Fmoc-Y(But)-D(But)-K(Boc)V-A- E(But)-COOH(SEQ ID NO：179)
26 residue substeps of fragment solid phase		Cl-TrT-resin (5mmol) 6.5g		6 equivalents	HBTU/HOBT			10	1.8 raw product protected 32
	Ac-D(But)-W-F-K(Boc)-A-F-COOH

(SEQ ID NO：1180)

Be combined to by solution again with the fragment that solid phase method produced

Fragment 1 Wang resin.C holds six peptides (carrying out aminolysis).Quantitative yield.

NH ₂-K (Boc)-F-K (Boc)-E (But)-A-F-Wang resin (SEQ ID NO:1181)

NH ₂-K(Boc)-F-K(Boc)-E(But)-A-F-CO-NH ₂(SEQ ID NO：1182)

Adopt DIC/HOBT to make above-mentioned fragment 2 and fragment 1

Coupling in DMF solution.

Fmoc-Y (But)-D (But)-K (Bpc)-V-A-E (But)-K (Boc)-F-K (Boc)-E (But)-F-CO-NH ₂The feature of (SEQ ID NO:1183) 12 residue peptide is to be free peptide after sloughing protecting group.Yield 50%

Slough Fmoc on above-mentioned 12 residues with the DMF solution (20%) of piperidines.After the drying, adopt the DMF solution of DCl/HOBT to make peptide and fragment 3 couplings.

Ac-D(But)-W-F-K(Boc)-A-F-Y(But)-D(but)-K(Boc)-V-A-E(But)-K(Boc)-F-K(Boc)-E(But)-A-FCO-NH ₂(SEQ ID NO：1184)

The yield of protected peptide is quantitative.

Mixture with TFA (80%), phenol (5%), thioanisole (5%), water (5%), tri isopropyl silane (TIS, 5%) stirred 90 minutes, sloughed protecting group.

Use ether sedimentation, with C-4 HPLC column purification.Yield 25%.

B) synthetic schemes describes in detail

1. the fragment condensation that synthesizes D-4F

[0326] the synthetic fragment that is used for the solid phase fragment condensation be:

Fragment 1:Ac-D (OBut)-W-F-K (ε Boc)-A-F-COOH (SEQ ID NO:1185);

Fragment 2:Fmoc-Y (OBut)-D (OBut)-K (ε Boc)-V-A-E (OBut)-COOH (SEQ IDNO:1186); With

Fragment 3:Fmoc-K (ε Boc) F-K (ε Boc)-E (OBut)-A-F-Rink amide resin (SEQ IDNO:1187).

[0327] after TFA handled, fragment 1 was retained on the resin, obtains final peptide amide.

[0328] for synthetic fragment 1: at the DMF of 6 equivalent DIEA: dichloromethane (1: 1) in the presence of, Fmoc-Phe (1.2 equivalent) is joined on the chlorine trityl resin (NovaBiochem, 1.3mmol/g replacement, use 5mmol or 6.5g), stirred 4 hours.Remaining functional group uses the methanol end-blocking on the resin in the presence of dichloromethane and DIEA.After sloughing Fmoc, add Fmoc amino acid derivativges (2 equivalent) and use aforesaid HOBt/HBTU reagent.Final Fmoc-D (OBut)-W-F-K (ε Boc)-A-F chlorine trityl resin is handled with the agent of Fmoc deblocking, in the presence of diisopropylethylamine, with 6 equivalent acetic anhydride acetylations.Gained Ac-D (OBut)-W-F-K (ε Boc)-A-F-resin was handled 4 hours under room temperature with the mixture (2: 2: 6, the 10ml/g resin) of trifluoroethanol-acetic acid-dichloromethane.Remove resin after filtration, remove with the normal hexane azeotropic distillation under the vacuum and desolvate.Residue (1.8g) is determined as Ac-D (OBut)-W-F-K (ε Boc)-A-F-COOH (SEQ ID NO:1188) with mass spectral analysis.

[0329] with fragment 1 described method, obtains fragment 2, Fmoc-Y (OBut)-D (OBut)-K (ε Boc)-V-A-E (OBut)-COOH (SEQ ID NO:1189).Ultimate yield is 2.2g.

[0330] fragment 3, use 0.9g (0.5mmol) Rink amide resin (NovaBiochem), obtain fragment.The Rink amide resin is handled secondary with the dichloromethane of 20% piperidines, 5 minutes first time, 15 minutes (Fmoc deblocking reagent) for the second time.Make 1.2 equivalent Fmoc-Phe condensations (amino acid condensation) with condensing agent HOBt/HBTU (2 equivalents add several diisopropylethylamine).Continue all the other amino acid whose deblocking and condensations, obtain Fmoc-K (ε Boc) F-K (ε Boc)-E (OBut)-A-F-rink amide resin (SEQ ID NO:1190).Cracking Fmoc, peptide resin K (ε Boc) F-K (ε Boc)-E (OBut)-A-F-rink amide resin (SEQID NO:1190) is used for fragment condensation as described below.

[0331] the DMF solution with fragment 2 joins in the fragment 3 (1.2 equivalent), adopts the HOBt-HBTU method, spends the night in the presence of DIEA.Resin with DMF washing and deblocking after, Fmoc-fragment 1 (1.2 equivalent) is joined in the dodecapeptide resin, employing HOBt-HBTU method is spent the night.

[0332] final peptide resin (3.3g) was with TFA-phenol-tri isopropyl silane-thioanisole-water (80: 5: 5: mixture process 5) 1.5 hours (10ml reagent/g resin).Leach resin, solution dilutes with the ether of 10 times of volumes.Precipitation of peptides with centrifugalize after, use the ether washed twice.The rough peptide of 1g carries out purification with HPLC, obtains the 100mg peptide.

2. the sign of peptide

[0333] peptide is identified with mass spectrum and analytical type HPLC method.

[0334] as shown in figure 14, solution is combined to the product of flow process in apo E nude mouse, and biological activity is very high when HDL that produces the inductive monocyte chemotaxis of inhibition LDL and preceding β HDL.Give the ApoE nude mouse above-mentioned synthetic D-4F of 5 micrograms (Frgmnt) that feed, perhaps give the mice pellet (Chow) of the no D-4F of mice equivalent.After feeding 12 hours, give the mice blood-letting, blood plasma FPLC fractionated.LDL (100 microgram LDL-cholesterol) is joined in the human artery parietal cell coculture with following composition: only (LDL) or contrast people HDL (contrast HDL) or derive from mice HDL (50 microgram HDL-cholesterol) or the post-HDL (pHDL that supplies with D-4F (Frgmnt) or do not supply with D-4F (Chow); Preceding β HDL), measure the monocyte chemotactic activity that is produced.

Embodiment 4 D-4F and the active comparison of reverse D-4F

[0335] as shown in figure 16, the biological activity of D-4F and reverse RD-4F does not have significant difference.Female apoE nude mouse is dissolved in 0 microgram, 3 micrograms, 6 micrograms, 12 micrograms or 25 microgram D-4F or the reverse D-4F solution of 100 microliters of water by stomach tube.Obtain blood after 7 hours, blood plasma FPLC fractionated.Standard control people LDL is joined in the human artery parietal cell by the concentration of the LDL-cholesterol/ml (LDL) of 100 micrograms.With the active normalizing to 1.0 of gained monocyte chemotactic.With same LDL with same concentrations, with derive from normal person (hHDL) or derive from give D-4F or oppositely the HDL of the apoE nude mouse of D-4F join in the human artery parietal cell by 50 microgram HDL-cholesterol/ml, D-4F or oppositely D-4F dosage shown in X-axis.Make gained monocyte chemotactic activity be normalized to the activity that adds LDL and do not add HDL.Institute's value is the HDL inflammation index.Shown result is the meansigma methods ± S.D of three independent experiment data.

[0336] should be understood that, embodiment described herein and embodiment only are used for illustrative purpose, those skilled in the art will propose various modifications or variation whereby, and these modifications or variation are also included within the scope of the application's spirit and scope and appended claims.The publication that all this paper quoted, patent and patent application all are attached to by reference and are used for all purposes herein.

Claims (36)

1. peptide that improves the atherosclerosis shape, wherein said peptide comprises the aminoacid sequence or the reverse aminoacid sequence of peptide in the listed peptide of table 4, table 5 or table 6.

2. the peptide of claim 1, wherein said peptide also comprise with N end or C holds link coupled protecting group.

3. the peptide of claim 1, wherein said peptide also comprises with N to be held link coupled first protecting group and holds link coupled second protecting group with C.

4. the peptide of claim 2; wherein said protecting group is to be selected from following protecting group: acetyl group; the alkyl of an amide groups and 3-20 carbon atom; Fmoc; Tboc; 9-fluorenes acetyl group; 1-fluorenes carboxyl; 9-fluorenes carboxyl; 9-Fluorenone-1-carboxyl; benzyloxycarbonyl; xanthyl (Xan); trityl (Trt); 4-methyl trityl (Mtt); 4-methoxyl group trityl (Mmt); 4-methoxyl group-2; 3; 6-trimethyl-benzenesulfonyl (Mtr); -2-sulfonyl (Mts); 4; 4-dimethoxy benzhydryl (Mbh); tosyl (Tos); 2; 2; 5; 7; 8-pentamethyl benzo dihydropyran-6-sulfonyl (Pmc); 4-methyl-benzyl (MeBzl); 4-methoxy-benzyl (MeOBzl); benzyloxy (BzlO); benzyl (Bzl); benzoyl (Bz); 3-nitro-2-pyridine sulfenyl (Npys); 1-(4; 4-dimethyl-2; 6-dioxo cyclohexylidene) ethyl (Dde); 2; the 6-dichloro benzyl (2,6-DiCl-Bzl); 2-chlorine benzyloxycarbonyl (2-Cl-Z); 2-bromo-benzyloxy-carbonyl (2-Br-Z); benzyloxymethyl (Bom); tertbutyloxycarbonyl (Boc); cyclohexyloxy (cHxO); tert-butoxy methyl (Bum); tert-butoxy (tBuO); the tert-butyl group (tBu); acetyl group (Ac) and trifluoroacetyl group (TFA).

5. the peptide of claim 1, the one or more aminoacid that comprised in the wherein said peptide are " D " aminoacid.

6. the peptide of claim 1, all aminoacid that comprised in the wherein said peptide all are " D " aminoacid.

7. the peptide of claim 1, wherein said peptide are gone up acceptable excipient with the pharmacology and are mixed mutually.

8. the peptide of claim 1, wherein said peptide are gone up with the pharmacology and are suitable for the orally give mammal after acceptable excipient mixes mutually.

9. each peptide among the claim 2-8, wherein said peptide comprises with N holds link coupled protecting group, and described N end protecting group is to be selected from following protecting group: the alkyl of acetyl group, a propeonyl and 3-20 carbon atom.

10. the peptide of claim 9, wherein said peptide comprises with C holds link coupled protecting group, and described C end protecting group is an amide groups.

11. the peptide of claim 9, wherein said peptide comprises:

Hold link coupled first protecting group with N, wherein said protecting group is to be selected from following protecting group: the alkyl of acetyl group, a propeonyl and 3-20 carbon atom; With

Hold link coupled second protecting group with C, described C end protecting group is an amide groups.

12. the mammiferous angiopathy of treatment and/or be the disease of feature with the inflammatory reaction and/or form the method for the disease of feature that described method comprises with the oxidation activity intermediate:

Have the mammal that needs to comprise the aminoacid sequence of listed peptide in table 4, table 5 or the table 6 or the peptide of reverse aminoacid sequence, its consumption is enough to improve one or more symptoms of described disease.

13. the method for claim 12, wherein said administration are to realize by being selected from following approach: oral administration, nasal-cavity administration, rectally, peritoneal injection and intravascular injection, subcutaneous injection, percutaneous dosing and intramuscular injection.

14. the method for claim 12, wherein said activating agent be selected from following medication combined medication: the CETP inhibitor; FTY720; Certican; the DPP4 inhibitor; calcium channel blocker; ApoA1 derivant or analogies or agonist; the PPAR agonist; steroid; imatinib mesylate; cholesterol absorption blocade (Zetia); Vytorin; any renin angiotensin approach blocade; angiotensin ii receptor antagonist (DAIWEN etc.); ACE inhibitor; renin inhibitor; MR antagonist and aldosterone synthase inhibitors; β-blocade; alpha-adrenergic aceptor antagonist; lxr agonist; the FXR agonist; remove receptor B1 agonist; the ABCA1 agonist; adiponectin receptor agonist or adiponectin inducer; stearyl-coenzyme A desaturase I (SCD1) inhibitor; cholesterol synthetic inhibitor (non-inhibin class); Diacrylglycerol acyl transferase I (DGAT1) inhibitor; the acetyl-CoA carboxylase inhibitor 2; the PAI-1 inhibitor; the LP-PLA2 inhibitor; GLP-1; glucokinase activating agents; the CB-1 agonist; AGE inhibitor/clastogen; pkc inhibitor; antithrombotic drug/coagulant; aspirin; the adp receptor blocade is clopidogrel for example; factor Xa inhibitor; the GPIIb/IIIa inhibitor; factor VIIa inhibitors; warfarin; low molecular weight heparin; tissue factor inhibitor; anti-inflammatory drug; probucol and derivant be AGI-1067 etc. for example; the CCR2 antagonist; the CX3CR1 antagonist; the IL-1 antagonist; nitrate and NO donor and phosphodiesterase inhibitor.

15. comprise table 4, the peptide of the aminoacid sequence of listed peptide or reverse aminoacid sequence is selected from purposes in the following disease in treatment in table 5 or the table 6: atheromatous plaque forms, atherosclerotic lesion forms, myocardial infarction, apoplexy, congestive heart failure, the arteriole dysfunction, the arteriole disease, aging-related arteriole disease, Alzheimer dependency arteriole disease, chronic nephropathy dependency arteriole disease, hypertension dependency arteriole disease, multi-infarct dementia dependency arteriole disease, subarachnoid hemorrhage dependency arteriole disease, peripheral blood vessel, chronic obstructive disease of lung (COPD), emphysema, asthma, idiopathic pulmonary fibrosis, pulmonary fibrosis, adult respiratory distress syndrome, osteoporosis, Paget, coronary artery calcification, rheumatoid arthritis, polyarteritis nodosa, polymyalgia rheumatica, lupus erythematosus, multiple sclerosis, Wegner granulomatosis, central nervous system's vasculitis (CNSV), xerodermosteosis, scleroderma, polymyositis, the AIDS inflammatory reaction, bacterial infection, fungal infection, viral infection, parasitic infection, influenza, bird flu, viral pneumonia, the endotoxin shock syndrome, sepsis, sepsis syndrome, wound/wound, organ transplantation, transplant atherosclerosis, transplant rejection, corneal ulcer, chronic/the disunion wound, ulcerative colitis, reperfusion injury (preventing and/or treating), ischemia reperfusion damage (preventing and/or treating), spinal cord injury (alleviating effect), cancer, myeloma/multiple myeloma, ovarian cancer, breast carcinoma, colon cancer, osteocarcinoma, osteoarthritis, inflammatory bowel, allergic rhinitis, cachexia, diabetes, Alzheimer, implanting prosthetic, biomembrane forms, Crohn disease, dermatitis, acute and chronic eczema, psoriasis, contact dermatitis, scleroderma, type i diabetes, type ii diabetes, teenager disease type diabetes, the prevent diabetes outbreak, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, erection disturbance, degeneration of macula, multiple sclerosis, nephropathy, neuropathy, parkinson disease, peripheral blood vessel and meningitis.

16. comprise table 4, the peptide of the aminoacid sequence of listed peptide or reverse aminoacid sequence is used for the treatment of purposes in the medicine that is selected from following disease in preparation in table 5 or the table 6: atheromatous plaque forms, atherosclerotic lesion forms, myocardial infarction, apoplexy, congestive heart failure, the arteriole dysfunction, the arteriole disease, aging-related arteriole disease, Alzheimer dependency arteriole disease, chronic nephropathy dependency arteriole disease, hypertension dependency arteriole disease, multi-infarct dementia dependency arteriole disease, subarachnoid hemorrhage dependency arteriole disease, peripheral blood vessel, chronic obstructive disease of lung (COPD), emphysema, asthma, idiopathic pulmonary fibrosis, pulmonary fibrosis, adult respiratory distress syndrome, osteoporosis, Paget, coronary artery calcification, rheumatoid arthritis, polyarteritis nodosa, polymyalgia rheumatica, lupus erythematosus, multiple sclerosis, Wegner granulomatosis, central nervous system's vasculitis (CNSV), xerodermosteosis, scleroderma, polymyositis, the AIDS inflammatory reaction, bacterial infection, fungal infection, viral infection, parasitic infection, influenza, bird flu, viral pneumonia, the endotoxin shock syndrome, sepsis, sepsis syndrome, wound/wound, organ transplantation, transplant atherosclerosis, transplant rejection, corneal ulcer, chronic/the disunion wound, ulcerative colitis, reperfusion injury (preventing and/or treating), ischemia reperfusion damage (preventing and/or treating), spinal cord injury (alleviating effect), cancer, myeloma/multiple myeloma, ovarian cancer, breast carcinoma, colon cancer, osteocarcinoma, osteoarthritis, inflammatory bowel, allergic rhinitis, cachexia, diabetes, Alzheimer, implanting prosthetic, biomembrane forms, Crohn disease, dermatitis, acute and chronic eczema, psoriasis, contact dermatitis, scleroderma, type i diabetes, type ii diabetes, teenager disease type diabetes, the prevent diabetes outbreak, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, erection disturbance, degeneration of macula, multiple sclerosis, nephropathy, neuropathy, parkinson disease, peripheral blood vessel and meningitis.

17. one kind is used to deliver a medicament the intraluminal support of body, described support comprises Support frame and peptide, and wherein Support frame is included in wherein formed a plurality of storages storehouse, and peptide comprises the aminoacid sequence or the reverse aminoacid sequence of the listed peptide of table 4, table 5 or table 6.

18. the support of claim 17, wherein said activating agent is included in the polymer.

19. the support of claim 17, wherein said Support frame comprise a kind of in metallic substrates or the polymeric substrates.

20. comprising, the support of claim 17, wherein said Support frame substrate be selected from following material: rustless steel, nitinol, tantalum, MP35N alloy, platinum, titanium, suitable biocompatible alloy, suitable biocompatible polymer and their combination.

21. the support of claim 17, micropore is contained in wherein said storage storehouse.

22. the support of claim 21, the diameter of wherein said micropore is about below 20 microns.

23. the support of claim 21, about 20 microns to about 50 microns of the diameter range of wherein said micropore.

24. the support of claim 21, about 10 microns to about 50 microns of the depth bounds of wherein said micropore.

25. the support of claim 21, about 50 microns of the degree of depth of wherein said micropore.

26. the support of claim 21, wherein said micropore spread all on the entire bracket framework, described framework respectively has a perforate on the outer surface of the inner surface of support and support.

27. the support of claim 21, wherein also comprise: be configured in the cover layer on the Support frame inner surface, described cover layer wraps up at least a portion in whole hole, and the speed that discharges from the pharmaceutical polymer of Support frame inner surface for the control medicine provides barrier characteristics.

28. the support of claim 17, wherein said storage storehouse comprises along the passage of Support frame outer surface.

29. the support of claim 18, wherein said polymer comprise ground floor first pharmaceutical polymer with first pharmacy feature, described polymeric layer comprises second pharmaceutical polymer with second pharmacy feature.

30. the support of claim 18, described support also comprises at the barrier layer that contains between the activating agent polymer.

31. the support of claim 17, described support also comprises the conduit that is connected with Support frame.

32. the support of claim 31, wherein said conduit comprises the air bag that is used for expandable stent.

33. the support of claim 31, wherein said conduit comprise the sheath that withdraws from after the expansion of permission support.

34. a method of making the drug-polymer support, this method comprises: Support frame is provided; On Support frame, cut out a plurality of storages storehouse; The compositions that will comprise one or more peptides is applied at least one storage storehouse, and described peptide comprises the aminoacid sequence or the reverse aminoacid sequence of listed peptide in table 4, table 5 or the table 6; With composition dries.

35. the method for claim 34, this method also comprise polymeric layer is applied in the dry compositions; With the polymer drying.

36. a method for the treatment of angiopathy, this method comprises:

In the support implanting to human body lumen of vessels with claim 17;

Expandable stent; With

At least a activating agent is discharged from least one surface of support.

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