CN1781933A - Thymosin alpha 1 active segment cyclicpeptide analogue and its poly glycol derivative - Google Patents
Thymosin alpha 1 active segment cyclicpeptide analogue and its poly glycol derivative Download PDFInfo
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- CN1781933A CN1781933A CNA2004100964592A CN200410096459A CN1781933A CN 1781933 A CN1781933 A CN 1781933A CN A2004100964592 A CNA2004100964592 A CN A2004100964592A CN 200410096459 A CN200410096459 A CN 200410096459A CN 1781933 A CN1781933 A CN 1781933A
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Abstract
The present invention relates to a kind of cyclopeptide derivative containing natural or artificial amino acid substituted active thymosin alpha-1 segemnt, and its preparation process, medicine composition and their medicines for treating or preventing diseases related to immune deficiency, hypoimmunity, etc.
Description
Invention field
The present invention relates to thymosin active fragments and cyclic peptide analogue natural or that alpha-non-natural amino acid replaces, and polyethylene glycol derivative, and preparation method thereof, contain their pharmaceutical composition and the purposes in the middle of diseases related such as treatment or prevention and immune deficiency, immunologic hypofunction thereof.
Background technology
Thymosin (T α 1) is a kind of important polypeptide para-immunity regulatory factor, effect with significant raise immunity is a kind of at the lymphocytic immunostimulant of T, can promote the ripe and differentiation of T cell, and impel the multiple lymphokine of sophisticated lymphocytic emiocytosis (as interleukin-2 and gamma-interferon etc.) can also promote the generation of interleukin-2 acceptor.T α 1 is made up of 28 amino-acid residues, molecular weight 3108, and iso-electric point 4.2, the N-end is the acetylize structure, its aminoacid sequence is as follows:
Ac-Ser-Asp-Ala-Ala-Val-Asp-Thr-Ser-Ser-Glu-Ile-Thr-Thr-Lys-Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu-Ala-Glu-Asp-OH
In recent years, the research of T α 1 mainly concentrates on clinical application, and is few about the research report of its structure activity relationship.1980, synthetic T α such as Wong
1With desAc-T α
1, suppress the E-RFT by external azathioprine and show their activity and natural T α
1Quite, T α is described
1The acetylize of N-end whether it is not actively had an influence.Remove report T α such as Frasca
1N-end fragment 1-14 can in adult rat (the 6-18 month) body, promote the IL-2 expression of receptor, strengthen outside the activity of helper T cell, other studies show that T α
1The essentially no activity of N-end fragment, C-end parts fragment has preferably active.Abiko etc. confirm T α with external E-RFT
1Some C-end fragment have the part activity: T α 1 (100%), 14-28 (9.83%), 19-28 (1.04%).Felix etc. confirm N-end fragment 1-4,4-10,1-10 and the basic non-activity of 1-14 with intravital immunosuppressed mice test; C-end fragment 15-28 and 18-28 and T α
1Quite active; 21-28 (75%), 23-28 (50%) and 25-28 (50%) have the part activity.Ciaredelli etc. confirm T α with external mixed lymphocytes proliferation test (MLC)
1C-end 20-26,25-27 and 25-28 have about 90% activity.Report C-end fragment 13-19 such as Ho and T α
1In external activity with identical short Cord blood T lymphocyte differentiation and maturation, 20-25 and 20-28 have the part activity.The external sulphur azoles purine of usefulness such as Ciaredelli suppresses the E-RFT and finds that C-end 17-28 area part fragment has active preferably.
Grottesi etc. by circular dichroism spectrum (CD) and 2D-NMR to T α
1Conformation in solution is studied, and the result shows: T α
1In the aqueous solution, do not form the secondary conformation of advantage, but in hydrophobic environment, can form certain secondary structure.In trifluoroethanol 40% (TFE) aqueous solution, Va
L5And Glu
8Between form β-corner, Lys
17And Glu
24Between form alpha-helix.Because T α
1Receptor structure is also still undiscovered, and Grottesi etc. infer T α
1With lymphocytic mechanism of action may be: T α
1At first form electrostatic interaction, induce Lys then by polare Aminosaeren residue and cytolemma
17To Glu
24Between sequence form α-Luo Xuanjiegou and embed cytolemma, and then stride the film district with the IL-2 acceptor electrostatic interaction take place.This action model helps to explain T α
1With the synergy of IL-2 in biological activity.
Type B viral hepatitis and hepatitis C can cause liver cirrhosis to cause liver cancer, and the whole world has 3.5 hundred million hepatitis b virus carriers and 1.5 hundred million hepatitis C carrier at present.China is hepatitis B big country, and the hepatitis B carriers more than 1.2 hundred million is arranged, and the hepatitis B patient more than 30,000,000 is arranged, the T α of chemosynthesis
1(Zadaxin) in 1996 at first in China listing, use separately or unite and use the treatment chronic hepatitis B with alpha-interferon.Zadaxin is equal to or is better than existing ethical goods in the curative effect aspect the treatment hepatitis B.Zadaxin all has certain curative effect for many other diseases (as hepatitis C, nonsmall-cell lung cancer, melanoma and acquired immune deficiency syndrome (AIDS) etc.).In addition, Zadaxin also can be used as the vaccine adjuvant, strengthens the immune effect of influenza vaccines and hepatitis B vaccine.At present, Zadaxin is just treated 3 clinical trial phases of HCV and 2 clinical trial phases of treatment liver cancer in the U.S., and 3 clinical trial phases of treatment HBV Japan carry out, and 2 clinical trial phases of treatment malignant melanoma carry out in Europe.This shows, research T α 1 and analogue thereof, seeking more efficiently, immunostimulant and antiviral drug have good prospect.
The present clinical T α 1 (Zadaxin) that uses is synthetic, costs an arm and a leg, dosage is big, the cycle is long, and therefore carrying out structure activity study finds that better analogue has application promise in clinical practice.Shortcomings such as the same with other peptide medicament, that T α 1 has is short such as the transformation period, easily be degraded in vivo, therefore T α 1 analogue of degraded has crucial meaning in active high, the antibody of design.
Summary of the invention:
The inventor and place laboratory study thereof have now found that T α 1 and derivative thereof have the biological activity of good preventing or treatment immune deficiency, immunologic hypofunction diseases related, the derivative that they and polyoxyethylene glycol form can keep the active while, prolonged the metabolic in vivo transformation period of compound of following (I), (IV), (VII), (VIII) group, thus reduced following (I), (IV), (VII), (VIII) group compound consumption and prolonged its action time in vivo.
Concrete, the present invention relates to T α as follows 1 active fragments derivative and steric isomer thereof.
One aspect of the present invention relates to tetrapeptide to ten an as described below peptide derivant and steric isomer thereof, and it is the compound of (I) group:
X
1-Y
1-Y
2-X
2
X
1-X
2-Y
1-Y
2-X
3
X
1-X
2-X
3-Y
1-Y
2-X
4
X
1-X
2-Y
1-Y
2-X
3-X
4
X
1-X
2-X
3-Y
1-Y
2-X
4-X
5
X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3
X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3
X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5
X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6
X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4
X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4
X
1-X
2-X
3-X
4-Y
1-Y
2-X
5
X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6
X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7
X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7
X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7(I)
Wherein, X
1, X
2, X
3, X
4, X
5, X
6, X
7Be natural or non-natural alkalescence, acidity or the aromatic amino acid and the derivative thereof of L-or D-type independently, described basic aminoacids is selected from Arg, Lys, Glu, Cys, His, Trp, Mob, Nal, Pya, Phe (X) and Phg (X), wherein X is optional single the replacement or two replacements of hydrogen, halogen, nitro, carboxyl or C1-C4 alkyl, and substituting group is selected from H, 4-F, 3-F, 2-F, 4-Cl, 2-Cl, 4-Br, 2-Br, 3-Br, 2,5-2Cl, 4-F, 3-Cl, 3-NO
2Acidic amino acid is selected from: Asp, Glu, His, Tyr, Trp, Mob, Nal, Pya and Phg (X), wherein X is optional single the replacement or two replacements of hydrogen, halogen, nitro, carboxyl or C1-C4 alkyl, and substituting group is selected from H, 4-F, 3-F, 2-F, 4-Cl, 2-Cl, 4-Br, 2-Br, 3-Br, 2,5-2Cl, 4-F, 3-Cl, 3-NO
2
Y
1, Y
2, Y
3, Y
4Independently be that the natural or non-natural of L-or D-type is neutral, lipotropy or aromatic amino acid and derivative thereof, be selected from Gly, Ala, β-Ala, GABA, Val, Leu, Ile, Pro, His, Tyr, Trp, Mob, Nal, Pya, Phe (X), Phg (X), wherein X is optional single the replacement or two replacements of hydrogen, halogen, nitro, carboxyl or C1-C4 alkyl, and substituting group is selected from H, 4-F, 3-F, 2-F, 4-Cl, 2-Cl, 4-Br, 2-Br, 3-Br, 2,5-2Cl, 4-F, 3-Cl, 3-NO
2
Another aspect of the present invention relates to tetrapeptide to ten an as described below peptide derivant and steric isomer thereof, the amino process PEG modification in site arbitrarily in the compound in wherein above-mentioned (I) group, become the compound shown in following (II) group, wherein said amino comprises the amino and amino acid side chain amino of N-end:
[PEG-X-(CH
2)
MCO-NH]
Z-X
1-Y
1-Y
2-X
2
[PEG-X-(CH
2)
MCO-NH]
Z-X
1-X
2-Y
1-Y
2-X
3
[PEG-X-(CH
2)
MCO-NH]
Z-X
1-X
2-X
3-Y
1-Y
2-X
4
[PEG-X-(CH
2)
MCO-NH]
Z-X
1-X
2-Y
1-Y
2-X
3-X
4
[PEG-X-(CH
2)
MCO-NH]
Z-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5
[PEG-X-(CH
2)
MCO-NH]
Z-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3
[PEG-X-(CH
2)
MCO-NH]
Z-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3
[PEG-X-(CH
2)
MCO-NH]
Z-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5
[PEG-X-(CH
2)
MCO-NH]
Z-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6
[PEG-X-(CH
2)
MCO-NH]
Z-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4
[PEG-X-(CH
2)
MCO-NH]
Z-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4
[PEG-X-(CH
2)
MCO-NH]
Z-X
1-X
2-X
3-X
4-Y
1-Y
2-X
5
[PEG-X-(CH
2)
MCO-NH]
Z-X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6
[PEG-X-(CH
2)
MCO-NH]
Z-X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7
[PEG-X-(CH
2)
MCO-NH]
Z-X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7
[PEG-X-(CH
2)
MCO-NH]
Z-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7(II)
Wherein PEG represents: RO (CH
2CH
2O)
n-CH
2CH
2, R=H or C and CH
3, n=5-1000 wherein; X=O, NH or NHCO; M=0-6; Z=1-3, X
1, X
2, X
3, X
4, X
5, X
6, X
7, Y
1, Y
2, Y
3, Y
4Definition as noted above.
Another aspect of the present invention relates to tetrapeptide to ten an as described below peptide derivant and steric isomer thereof, wherein the carboxyl in any site of (I) group compound is the compound that (III) as follows organizes through the PEG covalent modification, wherein said carboxyl comprises C-end carboxyl, aspartic acid and L-glutamic acid side chain carboxyl group:
[PEG-X-CO]
z-X
1-Y
1-Y
2-X
2
[PEG-X-CO]
z-X
1-X
2-Y
1-Y
2-X
3
[PEG-X-CO]
z-X
1-X
2-X
3-Y
1-Y
2-X
4
[PEG-X-CO]
z-X
1-X
2-Y
1-Y
2-X
3-X
4
[PEG-X-CO]
z-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5
[PEG-X-CO]
z-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3
[PEG-X-CO]
z-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3
[PEG-X-CO]
z-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5
[PEG-X-CO]
z-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6
[PEG-X-CO]
z-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4
[PEG-X-CO]
z-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4
[PEG-X-CO]
z-X
1-X
2-X
3-X
4-Y
1-Y
2-X
5
[PEG-X-CO]
z-X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6
[PEG-X-CO]
z-X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7
[PEG-X-CO]
z-X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7
[PEG-X-CO]
z-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7(III)
X wherein
1, X
2, Y
1, Y
2, X
3, X
4, X
5, X
6, X
7, Y
1, Y
2, Y
3, Y
4State as defined above shown in, X=O or NH, Z=1-3.
Another aspect of the present invention relates to tetrapeptide to ten an as described below peptide derivant and steric isomer thereof, wherein in optional position in the peptide sequence shown in (I) group compound, comprise in N end and C end and the peptide fragment and introduce halfcystine, form the compound of (IV) group as follows:
Cys-X
1-Y
1-Y
2-X
2
Cys-X
1-X
2-Y
1-Y
2-X
3
Cys-X
1-X
2-X
3-Y
1-Y
2-X
4
Cys-X
1-X
2-Y
1-Y
2-X
3-X
4
Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5
Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3
Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3
Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5
Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6
Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4
Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4
Cys-X
1-X
2-X
3-X
4-Y
1-Y
2-X
5
Cys-X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6
Cys-X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7
Cys-X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7
Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7(IV)
Another aspect of the present invention relates to tetrapeptide to ten an as described below peptide derivant and steric isomer thereof, it is further modified the back with compound of described (IV) group through the method that is selected from PEG-MAL, PEG-VS and PEG-IODS and forms the compound that (V) as follows organizes, and wherein PEG can be chain, starlike, ring-type, multi-arm type structure:
PEG-M-Cys-X
1-Y
1-Y
2-X
2
PEG-M-Cys-X
1-X
2-Y
1-Y
2-X
3
PEG-M-Cys-X
1-X
2-X
3-Y
1-Y
2-X
4
PEG-M-Cys-X
1-X
2-Y
1-Y
2-X
3-X
4
PEG-M-Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5
PEG-M-Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3
PEG-M-Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3
PEG-M-Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5
PEG-M-Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6
PEG-M-Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4
PEG-M-Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4
PEG-M-Cys-X
1-X
2-X
3-X
4-Y
1-Y
2-X
5
PEG-M-Cys-X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6
PEG-M-Cys-X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7
PEG-M-Cys-X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7
PEG-M-Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7(V)，
Wherein
Cys is a halfcystine, links to each other with M group covalency by the side chain sulphur atom; X
1, X
2, Y
1, Y
2, X
3, X
4, X
5, X
6, X
7, Y
1, Y
2, Y
3, Y
4State as defined above.
Another aspect of the present invention relates to tetrapeptide to ten an as described below peptide derivant and steric isomer thereof, wherein introduce Electron Affinities group or nucleophilic group at the C end of the compound of described (I) group, and it is corresponding to opposite nucleophilic group or the Electron Affinities group of N end introducing, obtain the compound of (VI) group as follows, wherein said nucleophilic reagent is selected from the iodine negative ion, water, the hydroxyl negative ion, the methoxyl group negative ion, the ethanoyl negative ion, amino, the nitrate radical negative ion, the nitrite anions negative ion, the azido-negative ion, the cyano group negative ion, 1-proyl negative ion, the dimethyl malonate negative ion, the sulfydryl negative ion, the methylthio group negative ion, the thiocyanogen negative ion, dimethyl sulphide, front three phosphorus; Described electrophilic reagent is selected from thiocarboxyl group acetyl ammonia, halogen, mineral acid, organic acid, aldehyde, active ketone, carboxylic acid, ester, nitro-compound:
Z
1-X
1-Y
1-Y
2-X
2-Z
2
Z
1-X
1-X
2-Y
1-Y
2-X
3-Z
2
Z
1-X
1-X
1-X
2-X
3-Y
1-Y
2-X
4-Z
2
Z
1-X
1-X
2-Y
1-Y
2-X
3-X
4-Z
2
Z
1-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Z
2
Z
1-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-Z
2
Z
1-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4-Z
2
Z
1-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4-Z
2
Z
1-X
1-X
2-X
3-X
4-Y
1-Y
2-X
5-Z
2
Z
1-X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6-Z
2
Z
1-X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7-Z
2
Z
1-X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7-Z
2
Z
1-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7-Z
2(VI)，
Z wherein
1And Z
2Be one group of amino-acid residue or other fragment, work as Z with nucleophilic group and Electron Affinities group
1Z2 has the Electron Affinities group when having nucleophilic group, works as Z
1Z when having the Electron Affinities group
2Have nucleophilic group.
Preferably, above-mentioned tetrapeptide to ten peptide derivant and steric isomer thereof, it is:
CEVVE-SCH
2CH
2CONH
2
CKEVVE-SCH
2CH
2CONH
2
CKKEVVE-SCH
2CH
2CONH
2
CKEVVEE-SCH
2CH
2CONH
2
CEKKEVVE-SCH
2CH
2CONH
2
CKEKKEVVE-SCH
2CH
2CONH
2
CKEVVEKEVVE-SCH
2CH
2CONH
2
CKEVVEEAE-SCH
2CH
2CONH
2
CKEVVEEA-SCH
2CH
2CONH
2, or
CKEVVEEAEN-SCH
2CH
2CONH
2。
Another aspect of the present invention relates to tetrapeptide to ten an as described below peptide derivant and steric isomer thereof, wherein (IV) and (VI) any site of the compound of group introduce aliphatic chain, aliphatic ether chain, thioether chain, amino acid and other flexible chain-like structure unit, obtain the compound of (VII) group as follows:
Cys-L
n-X
1-Y
1-Y
2-X
2
Cys-L
n-X
1-X
2-Y
1-Y
2-X
3
Cys-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4
Cys-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4
Cys-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5
Cys-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3
Cys-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3
Cys-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5
Cys-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6
Cys-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4
Cys-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4
Cys-L
n-X
1-X
2-X
3-X
4-Y
1-Y
2-X
5
Cys-L
n-X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6
Cys-L
n-X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7
Cys-L
n-X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7
Cys-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7，
Or following structure:
Z
1-L
n-X
1-Y
1-Y
2-X
2-Z
2
Z
1-L
n-X
1-X
2-Y
1-Y
2-X
3-Z
2
Z
1-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-Z
2
Z
1-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4-Z
2
Z
1-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Z
2
Z
1-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-Z
2
Z
1-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4-Z
2
Z
1-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4-Z
2
Z
1-L
n-X
1-X
2-X
3-X
4-Y
1-Y
2-X
5-Z
2
Z
1-L
n-X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6-Z
2
Z
1-L
n-X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7-Z
2
Z
1-X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7-Z
2
Z
1-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7-Z
2(VII)
Wherein, L represents the chain-like structure unit of any flexibility, n=1-4, the site, L place shown in the above general formula is not the unique site that can introduce, L can be in peptide sequence the optional position except that two ends.
Preferably, tetrapeptide to ten peptide derivant of the present invention and steric isomer thereof, it comprises:
CLEVVE
CLKEVVE
CLKKEVVE
CLKEVVEE
CLEKKEVVE
CLKEKKEVVE
CLKEVVEKEVVE
CLKEVVEEAE
CLKEVVEEA
CLKEVVEEAEN
CLLEVVE
CLLKEVVE
CLLKKEVVE
CLLKEVVEE
CLLEKKEVVE
CLLKEKKEVVE
CLLKEVVEKEVVE
CLLKEVVEEAE
CLLKEVVEEA
CLLKEVVEEAEN，
Or the compound of following structure:
CLEVVE-SCH
2CH
2CONH
2
CLKEVVE-SCH
2CH
2CONH
2
CLKKEVVE-SCH
2CH
2CONH
2
CLKEVVEE-SCH
2CH
2CONH
2
CLEKKEVVE-SCH
2CH
2CONH
2
CLKEKKEVVE-SCH
2CH
2CONH
2
CLKEVVEKEVVE-SCH
2CH
2CONH
2
CLKEVVEEAE-SCH
2CH
2CONH
2
CLKEVVEEA-SCH
2CH
2CONH
2
CLKEVVEEAEN-SCH
2CH
2CONH
2
CLLEVVE-SCH
2CH
2CONH
2
CLLKEVVE-SCH
2CH
2CONH
2
CLLKKEVVE-SCH
2CH
2CONH
2
CLLKEVVEE-SCH
2CH
2CONH
2
CLLEKKEVVE-SCH
2CH
2CONH
2
CLLKEKKEVVE-SCH
2CH
2CONH
2
CLLKEVVEKEVVE-SCH
2CH
2CONH
2
CLLKEVVEEAE-SCH
2CH
2CONH
2
CLLKEVVEEA-SCH
2CH
2CONH
2
CLLKEVVEEAEN-SCH
2CH
2CONH
2, wherein, L=-NHCH
2CH
2OCH
2COO-.
Another aspect of the present invention relates to tetrapeptide to ten an as described below peptide derivant and steric isomer thereof, wherein the compound with arbitrary aforementioned (I), (IV), (VII) group carries out cyclization with any known cyclization method, obtains the ring compound shown in (VIII) group:
Ring (X
1-Y
1-Y
2-X
2)
Ring (X
1-X
2-Y
1-Y
2-X
3)
Ring (X
1-X
2-X
3-Y
1-Y
2-X
4)
Ring (X
1-X
2-Y
1-Y
2-X
3-X
4)
Ring (X
1-X
2-X
3-Y
1-Y
2-X
4-X
5)
Ring (X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3)
Ring (X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3)
Ring (X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5)
Ring (X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6)
Ring (X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4)
Ring (X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4)
Ring (X
1-X
2-X
3-X
4-Y
1-Y
2-X
5)
Ring (X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6)
Ring (X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7)
Ring (X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7)
Ring (X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7)
Or following structure:
Ring (Cys-X
1-Y
1-Y
2-X
2)
Ring (Cys-X
1-X
2-Y
1-Y
2-X
3)
Ring (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4)
Ring (Cys-X
1-X
2-Y
1-Y
2-X
3-X
4)
Ring (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5)
Ring (Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3)
Ring (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3)
Ring (Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5)
Ring (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6)
Ring (Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4)
Ring (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4)
Ring (Cys-X
1-X
2-X
3-X
4-Y
1-Y
2-X
5)
Ring (Cys-X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6)
Ring (Cys-X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7)
Ring (Cys-X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7)
Or following compound:
Ring (Z
1-L
n-X
1-Y
1-Y
2-X
2)
Ring (Z
1-L
n-X
1-X
2-Y
1-Y
2-X
3)
Ring (Z
1-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4)
Ring (Z
1-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4)
Ring (Z
1-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5)
Ring (Z
1-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3)
Ring (Z
1-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4)
Ring (Z
1-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4)
Ring (Z
1-L
n-X
1-X
2-X
3-X
4-Y
1-Y
2-X
5)
Ring (Z
1-L
n-X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6)
Ring (Z
1-L
n-X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7)
Ring (Z
1-L
n-X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7)
Ring (Z
1-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7) (VIII)
Wherein, X
1, X
2, Y
1, Y
2, X
3, X
4, X
5, X
6, X
7, Y
1, Y
2, Y
3, Y
4State as defined above shown in, Z
1State as defined above shown in, L
nState as defined above shown in.
Preferably, tetrapeptide to ten peptide derivant of the present invention and steric isomer thereof, it is following structure:
Ring (EVVE)
Ring (KEVVE)
Ring (KKEVVE)
Ring (KEVVEE)
Ring (EKKEVVE)
Ring (KEKKEVVE)
Ring (KEVVEKEVVE)
Ring (KEVVEEAE)
Ring (KEVVEEA)
Ring (KEVVEEAEN)
Or
Ring (CEVVE)
Ring (CKEVVE)
Ring (CKKEVVE)
Ring (CKEVVEE)
Ring (CEKKEVVE)
Ring (CKEKKEVVE)
Ring (CKEVVEKEVVE)
Ring (CKEVVEEAE)
Ring (CKEVVEEA)
Ring (CKEVVEEAEN)
Or:
Ring (CLEVVE)
Ring (CLKEVVE)
Ring (CLKKEVVE)
Ring (CLKEVVEE)
Ring (CLEKKEVVE)
Ring (CLKEKKEVVE)
Ring (CLKEVVEKEVVE)
Ring (CLKEVVEEAE)
Ring (CLKEVVEEA)
Ring (CLKEVVEEAEN)
Or:
Ring (CLLEVVE)
Ring (CLLKEVVE)
Ring (CLLKKEVVE)
Ring (CLLKEVVEE)
Ring (CLLEKKEVVE)
Ring (CLLKEKKEVVE)
Ring (CLLKEVVEKEVVE)
Ring (CLLKEVVEEAE)
Ring (CLLKEVVEEA)
Ring (CLLKEVVEEAEN).
Another aspect of the present invention relates to tetrapeptide to ten an as described below peptide derivant and steric isomer thereof, the amino in any site is modified through PEG in the compound of wherein said (VIII) group, obtain the compound of (XI) as follows group, wherein said amino comprises the side chain amino of N-end amino and natural amino acid or alpha-non-natural amino acid
[PEG-X-(CH
2)
MCO-NH]
Z-ring (X
1-Y
1-Y
2-X
2)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (X
1-X
2-Y
1-Y
2-X
3)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (X
1-X
2-X
3-Y
1-Y
2-X
4)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (X
1-X
2-Y
1-Y
2-X
3-X
4)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (X
1-X
2-X
3-Y
1-Y
2-X
4-X
5)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (X
1-X
2-X
3-X
4-Y
1-Y
2-X
5)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (Cys-X
1-Y
1-Y
2-X
2)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (Cys-X
1-X
2-Y
1-Y
2-X
3)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (Cys-X
1-X
2-Y
1-Y
2-X
3-X
4)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (Cys-X
1-X
2-X
3-X
4-Y
1-Y
2-X
5)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (Cys-X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (Cys-X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (Cys-X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7)
Or:
[PEG-X-(CH
2)
MCO-NH]
Z-ring (Z
1-L
n-X
1-Y
1-Y
2-X
2)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (Z
1-L
n-X
1-X
2-Y
1-Y
2-X
3)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (Z
1-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (Z
1-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (Z
1-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (Z
1-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (Z
1-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (Z
1-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (Z
1-L
n-X
1-X
2-X
3-X
4-Y
1-Y
2-X
5)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (Z
1-L
n-X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (Z
1-L
n-X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (Z
1-L
n-X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7)
[PEG-X-(CH
2)
MCO-NH]
Z-ring (Z
1-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7) (XI),
Wherein said PEG represents: RO (CH
2CH
2O)
n-CH
2CH
2, R=H or C and CH
3, n=5-1000; X=O, NH or NHCO; M=0-6; Z=1-3, X
1, X
2, Y
1, Y
2, X
3, X
4, X
5, X
6, X
7, Y
1, Y
2, Y
3, Y
4State as defined above shown in, Z
1, L
nState as defined above shown in.
Another aspect of the present invention relates to tetrapeptide to ten an as described below peptide derivant and steric isomer thereof, comprises following compound:
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CKEVVE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CKKEVVE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CKEVVEE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CEKKEVVE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CKEKKEVVE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CKEVVEKEVVE)
PEG-CH
2CH
2-X-(CH
2) xCO-encircles (CKEVVEEAE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CKEVVEEA)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CKEVVEEAEN)
Or following structure:
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CL KEVVE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLKKEVVE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLKEVVEE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLEKKEVVE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLKEKKEVVE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLKEVVEKEVVE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLKEVVEEAE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLKEVVEEA)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLKEVVEEAEN)
Or the compound of following structure:
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLLKEVVE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLLKKEVVE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLLKEVVEE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLLEKKEVVE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLLKEKKEVVE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLLKEVVEKEVVE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLLKEVVEEAE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLLKEVVEEA)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLLKEVVEEAEN)
Wherein, X=O, NH or NHCO; M=0-6.
Another aspect of the present invention relates to tetrapeptide to ten an as described below peptide derivant and steric isomer thereof, the wherein carboxyl process PEG modification in site arbitrarily in the compound of (VIII) group, obtain the compound shown in following (IX), wherein said amino comprises the side chain carboxyl group of C-end amino and natural amino acid or alpha-non-natural amino acid:
[PEG-X-CO]
z-ring (X
1-Y
1-Y
2-X
2)
[PEG-X-CO]
z-ring (X
1-X
2-Y
1-Y
2-X
3)
[PEG-X-CO]
z-ring (X
1-X
2-X
3-Y
1-Y
2-X
4)
[PEG-X-CO]
z-ring (X
1-X
2-Y
1-Y
2-X
3-X
4)
[PEG-X-CO]
z-ring (X
1-X
2-X
3-Y
1-Y
2-X
4-X
5)
[PEG-X-CO]
z-ring (X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3)
[PEG-X-CO]
z-ring (X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3)
[PEG-X-CO]
z-ring (X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5)
[PEG-X-CO]
z-ring (X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6)
[PEG-X-CO]
z-ring (X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4)
[PEG-X-CO]
z-ring (X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4)
[PEG-X-CO]
z-ring (X
1-X
2-X
3-X
4-Y
1-Y
2-X
5)
[PEG-X-CO]
z-ring (X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6)
[PEG-X-CO]
z-ring (X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7)
[PEG-X-CO]
z-ring (X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7)
[PEG-X-CO]
z-ring (X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7)
[PEG-X-CO]
z-ring (Cys-X
1-Y
1-Y
2-X
2)
[PEG-X-CO]
z-ring (Cys-X
1-X
2-Y
1-Y
2-X
3)
[PEG-X-CO]
z-ring (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4)
[PEG-X-CO]
z-ring (Cys-X
1-X
2-Y
1-Y
2-X
3-X
4)
[PEG-X-CO]
z-ring (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5)
[PEG-X-CO]
z-ring (Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3)
[PEG-X-CO]
z-ring (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3)
[PEG-X-CO]
z-ring (Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5)
[PEG-X-CO]
z-ring (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6)
[PEG-X-CO]
z-ring (Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4)
[PEG-X-CO]
z-ring (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4)
[PEG-X-CO]
z-ring (Cys-X
1-X
2-X
3-X
4-Y
1-Y
2-X
5)
[PEG-X-CO]
z-ring (Cys-X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6)
[PEG-X-CO]
z-ring (Cys-X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7)
[PEG-X-CO]
z-ring (Cys-X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7)
Or following structure:
[PEG-X-CO]
z-ring (Z
1-L
n-X
1-Y
1-Y
2-X
2)
[PEG-X-CO]
z-ring (Z
1-L
n-X
1-X
2-Y
1-Y
2-X
3)
[PEG-X-CO]
z-ring (Z
1-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4)
[PEG-X-CO]
z-ring (Z
1-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4)
[PEG-X-CO]
z-ring (Z
1-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5)
[PEG-X-CO]
z-ring (Z
1-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3)
[PEG-X-CO]
z-ring (Z
1-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4)
[PEG-X-CO]
z-ring (Z
1-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4)
[PEG-X-CO]
z-ring (Z
1-L
n-X
1-X
2-X
3-X
4-Y
1-Y
2-X
5)
[PEG-X-CO]
z-ring (Z
1-L
n-X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6)
[PEG-X-CO]
z-ring (Z
1-L
n-X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7)
[PEG-X-CO]
z-ring (Z
1-X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7)
[PEG-X-CO]
z-ring (Z
1-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7) (IX)
Wherein, X
1, X
2, Y
1, Y
2, X
3, X
4, X
5, X
6, X
7, Y
1, Y
2, Y
3, Y
4Definition shown in claim 1, Z
1, L
nState as defined above shown in; X=O or NH, Z=1-3.
Another aspect of the present invention relates to tetrapeptide to ten an as described below peptide derivant and steric isomer thereof, is selected from:
[PEG-X-CO]
z-ring (EVVE)
[PEG-X-CO]
zRing (KEVVE)
[PEG-X-CO]
zRing (KKEVVE)
[PEG-X-CO]
zRing (KEVVEE)
[PEG-X-CO]
zRing (EKKEVVE)
[PEG-X-CO]
zRing (KEKKEVVE)
[PEG-X-CO]
zRing (KEVVEKEVVE)
[PEG-X-CO]
zRing (KEVVEEAE)
[PEG-X-CO]
zRing (KEVVEEA)
[PEG-X-CO]
zRing (KEVVEEAEN)
[PEG-X-CO]
z-ring (CEVVE)
[PEG-X-CO]
zRing (CKEVVE)
[PEG-X-CO]
zRing (CKKEVVE)
[PEG-X-CO]
zRing (CKEVVEE)
[PEG-X-CO]
zRing (CEKKEVVE)
[PEG-X-CO]
zRing (CKEKKEVVE)
[PEG-X-CO]
zRing (CKEVVEKEVVE)
[PEG-X-CO]
zRing (CKEVVEEAE)
[PEG-X-CO]
zRing (CKEVVEEA)
[PEG-X-CO]
zRing (CKEVVEEAEN)
Or following structure:
[PEG-X-CO]
zRing (CLEVVE)
[PEG-X-CO]
zRing (CLKEVVE)
[PEG-X-CO]
zRing (CLKKEVVE)
[PEG-X-CO]
zRing (CLKEVVEE)
[PEG-X-CO]
zRing (CLEKKEVVE)
[PEG-X-CO]
zRing (CLKEKKEVVE)
[PEG-X-CO]
zRing (CLKEVVEKEVVE)
[PEG-X-CO]
zRing (CLKEVVEEAE)
[PEG-X-CO]
zRing (CLKEVVEEA)
[PEG-X-CO]
zRing (CLKEVVEEAEN)
Or the compound of following structure:
[PEG-X-CO]
zRing (CLLEVVE)
[PEG-X-CO]
zRing (CLLKEVVE)
[PEG-X-CO]
zRing (CLLKKEVVE)
[PEG-X-CO]
zRing (CLLKEVVEE)
[PEG-X-CO]
zRing (CLLEKKEVVE)
[PEG-X-CO]
zRing (CLLKEKKEVVE)
[PEG-X-CO]
zRing (CLLKEVVEKEVVE)
[PEG-X-CO]
zRing (CLLKEVVEEAE)
[PEG-X-CO]
zRing (CLLKEVVEEA)
[PEG-X-CO]
zRing (CLLKEVVEEAEN).
Another aspect of the present invention relates to tetrapeptide to ten an as described below peptide derivant and steric isomer thereof, after wherein halfcystine is introduced in compound optional position in peptide sequence or existing halfcystine position or sequence of (VIII) group, through being selected from PEG-MAL, the method of PEG-VS and PEG-IODS is modified, obtain the compound of (X) as follows group, wherein PEG can be chain, starlike, ring-type, multi-arm type structure:
PEG-M-encircles (Cys-X
1-Y
1-Y
2-X
2)
PEG-M-encircles (Cys-X
1-X
2-Y
1-Y
2-X
3)
PEG-M-encircles (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4)
PEG-M-encircles (Cys-X
1-X
2-Y
1-Y
2-X
3-X
4)
PEG-M-encircles (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5)
PEG-M-encircles (Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3)
PEG-M-encircles (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3)
PEG-M-encircles (Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5)
PEG-M-encircles (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6)
PEG-M-encircles (Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4)
PEG-M-encircles (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4)
PEG-M-encircles (Cys-X
1-X
2-X
3-X
4-Y
1-Y
2-X
5)
PEG-M-encircles (Cys-X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6)
PEG-M-encircles (Cys-X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7)
PEG-M-encircles (Cys-X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7)
PEG-M-encircles (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7)
Also can be following structure:
PEG-M-encircles (Cys-L
n-X
1-Y
1-Y
2-X
2)
PEG-M-encircles (Cys-L
n-X
1-X
2-Y
1-Y
2-X
3)
PEG-M-encircles (Cys-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4)
PEG-M-encircles (Cys-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4)
PEG-M-encircles (Cys-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5)
PEG-M-encircles (Cys-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3)
PEG-M-encircles (Cys-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4)
PEG-M-encircles (Cys-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4)
PEG-M-encircles (Cys-L
n-X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7)
PEG-M-encircles (Cys-X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7)
PEG-M-encircles (Cys-L
n-X
1One X
2-X
3-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7)
PEG-M-encircles (Cys-L
n-X
1-X
2-X
3-X
4-Y
1-Y
2-X
5)
PEG-M-encircles (Cys-L
n-X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6) (X)
Wherein,
X wherein
1, Z
1Can be halfcystine, link to each other with M group covalency by the side chain sulphur atom; X
1, X
2, Y
1, Y
2, X
3, X
4, X
5, X
6, X
7, Y
1, Y
2, Y
3, Y
4State as defined above shown in, Z
1, L
nState as defined above shown in.
Another aspect of the present invention relates to tetrapeptide to ten an as described below peptide derivant and steric isomer thereof, and it is selected from:
[PEG-M]-ring (CEVVE)
[PEG-M]-ring (CKEVVE)
[PEG-M]-ring (CKKEVVE)
[PEG-M]-ring (CKEVVEE)
[PEG-M]-ring (CEKKEVVE)
[PEG-M]-ring (CKEKKEVVE)
[PEG-M] encircles (CKEVVEKEVVE)
[PEG-M] encircles (CKEVVEEAE)
[PEG-M]-ring (CKEVVEEA)
[PEG-M]-ring (CKEVVEEAEN)
Or following structure:
[PEG-M]-ring (CLEVVE)
[PEG-M]-ring (CLKEVVE)
[PEG-M]-ring (CLKKEVVE)
[PEG-M]-ring (CLKEVVEE)
[PEG-M]-ring (CLEKKEVVE)
[PEG-M]-ring (CLKEKKEVVE)
[PEG-M]-ring (CLKEVVEKEVVE)
[PEG-M]-ring (CLKEVVEEAE)
[PEG-M]-ring (CLKEVVEEA)
[PEG-M]-ring (CLKEVVEEAEN)
Or the compound of following structure:
[PEG-M]-ring (CLLEVVE)
[PEG-M]-ring (CLLKEVVE)
[PEG-M]-ring (CLLKKEVVE)
[PEG-M]-ring (CLLKEVVEE)
[PEG-M] encircles (CLLEKKEVVE)
[PEG-M]-ring (CLLKEKKEVVE)
[PEG-M]-ring (CLLKEVVEKEVVE)
[PEG-M]-ring (CLLKEVVEEAE)
[PEG-M]-ring (CLLKEVVEEA)
[PEG-M]-ring (CLLKEVVEEAEN).
The invention still further relates at least a be selected from above-mentioned (I), (II), (III),, the compound of (IV), (V), (VI), (VII), (VIII), (IX), (X) group or its arbitrary be combined in that preparation is used for the treatment of and/or the medicine of epidemic prevention defective or hypoimmunity diseases related in purposes.
The invention still further relates to pharmaceutical composition, comprising at least a compound that is selected from above-mentioned (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X) group, and pharmaceutical carrier or vehicle.
The invention still further relates to preparation above-mentioned (I), (II), (III),, the method for the compound of (IV), (V), (VI), (VII), (VIII), (IX), (X) group, it comprises with known solution method and solid phase method and synthesizing.
The used PEG-OH structure of the present invention is: RO (CH
2CH
2O) NCH
2CH
2OH, wherein R=H or CH
3, molecular-weight average can be used as commercialization reagent by the PEG-OH of hundreds of to several ten thousand and buys PEG-NH
2, PEG-NHCOCH
2CH
2COOH can obtain by following approach reaction:
Concrete, the amino acid in that the end elder generation of PEG introduces amino, carboxyl or preparation PEGization is coupled in the peptide sequence with solution method or solid-phase synthesis and goes, can realize the N-end amino to polypeptide, C-holds carboxyl, Lys side chain amino, the modification of Asp or Glu side chain carboxyl group is with PEG-NH
2With maleic anhydride, vinyl sulfoxide, iodo acetic anhydride can obtain PEG-MAL, PEG-VS, PEG-IODO.
Wang Resin involved in the present invention, MBHA Resin, DCC, HOBt, HBTU, BOP, Fmoc amino acid, BOC protect amino acid, and reagent such as TFA, DIEA, m PEG-OH, NMM all obtain by buying.All alpha-non-natural amino acids are synthetic and fractionation by this laboratory.
According to the present invention, have with immune deficiency or immunologic hypofunction diseases associated: hepatitis B, hepatitis C, nonsmall-cell lung cancer, melanoma, acquired immune deficiency syndrome (AIDS) etc.
According to the present invention, used term such as T α 1 (17-27) refer to the sequence of holding C-end corresponding position in T α 1 from N-.
The T α 1 active fragments derivative and the steric isomer thereof of (I)-(X) shown in the present group or contain its pharmaceutical composition can the unit dosage form administration, route of administration can be enteron aisle or non-enteron aisle, as oral, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritonaeum or rectum etc.
Form of administration is tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, suspensoid, emulsion, granule, liposome, transdermal agent, buccal tablet, suppository, lyophilized injectable powder etc. for example.Can be ordinary preparation, sustained release preparation, controlled release preparation and various particulate delivery system.
For the unit form of administration is made tablet, can be extensive use of various carrier well known in the art.About the example of carrier, comprise for example thinner and absorption agent, as starch, dextrin, lactose, N.F,USP MANNITOL, sucrose, glucose, calcium sulfate, sodium-chlor, urea, lime carbonate, white bole, Microcrystalline Cellulose, pure aluminium silicate etc.; Wetting agent and tackiness agent are as water, glycerine, polyoxyethylene glycol, ethanol, propyl alcohol, starch slurry, dextrin, syrup, honey, glucose solution, mucialga of arabic gummy, gelatine size, Xylo-Mucine, lac, methylcellulose gum, potassiumphosphate, polyvinylpyrrolidone etc.; Disintegrating agent is as dry starch, alginates, agar powder, laminaran, sodium bicarbonate and Citric Acid, lime carbonate, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.; The disintegration inhibitor is as sucrose, Tristearoylglycerol, theobroma oil, hydrogenation wet goods; Absorption enhancer is as quaternary ammonium salt, sodium lauryl sulphate etc.; Lubricant is as talcum powder, silicon-dioxide, W-Gum, stearate, boric acid, whiteruss, polyoxyethylene glycol etc.Tablet further can also be made coating tablet, as sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.For pill is made in the administration unit, can be extensive use of various carrier well known in the art.Example about carrier is, for example thinner and absorption agent are as glucose, lactose, starch, theobroma oil, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talcum powder etc.; Tackiness agent such as gum arabic, tragacanth gum, gelatin, ethanol, honey, rice paste or batter etc.; Disintegrating agent is as agar powder, dry starch, alginates, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.For suppository is made in the administration unit, can be extensive use of various carrier well known in the art.Example about carrier is, for example the ester of polyoxyethylene glycol, Yelkin TTS, theobroma oil, higher alcohols, higher alcohols, gelatin, semi-synthetic glyceryl ester etc.For capsule is made in the administration unit, effective constituent formula (I)-(X) T α 1 active fragments derivative or its steric isomer are mixed with above-mentioned various carriers, and the mixture that will obtain thus places hard capsule or soft capsule.Also tripeptide derivative or its steric isomer of effective constituent (I)-(X) group can be made microcapsule, be suspended in and make suspensoid in the aqueous medium, in the hard capsule of also can packing into or make injection and use.For injection preparation is made in the administration unit, as solution, emulsion, lyophilized injectable powder and suspensoid, can use this area all thinners commonly used, as water, ethanol, polyoxyethylene glycol, 1, the isooctadecanol of the isooctadecanol of ammediol, ethoxylation, polyoxy baseization, Polyoxyethylene Sorbitol Fatty Acid Esters etc.In addition, ooze injection liquid, can in injection preparation, add proper amount of sodium chloride, glucose or glycerine, in addition, can also add conventional solubility promoter, buffer reagent, pH regulator agent etc. in order to prepare etc.
In addition, as needs, also can in pharmaceutical preparation, add tinting material, sanitas, spices, correctives, sweeting agent or other material.
The compound of the present invention (I)-(X) group, the dosage of derivative or its steric isomer depends on many factors, for example to prevent or treat the character and the severity of the T α 1 active fragments derivative disease of (I)-(X) group, the sex of patient or animal, age, body weight and individual reaction, used particular compound, route of administration and administration number of times etc.Above-mentioned dosage can the single dose form or be divided into several, for example two, in, four dosage form administrations.
The abbreviation of Shi Yonging in the present invention has following implication:
| ?Ac | Ethanoyl | HOBt | I-hydroxybenzotriazole |
| ?Ala(A) | L-Ala | HOSu | N-hydroxy-succinamide |
| ?Alloc | Allyloxycarbonyl | IL | Interleukin- |
| ?Allyl | Allyl group | IFN | Interferon, rabbit |
| ?Asn(N) | N | X(？) | ?-S-CH 2CH 2CONH 2 |
| ?Asp(D) | Aspartic acid | Lys(K) | Methionin |
| ?Boc | Tertbutyloxycarbonyl | NK | Natural killer |
| ?Bzl | Benzyl | OD | Optical density(OD) |
| ?PMeOBzl | To methoxy-benzyl | Y(？) | ?-NHCH 2CH 2OCH 2COO- |
| ?tBU | Tertbutyloxycarbonyl | MPEG | Mono methoxy polyethylene glycol |
| ?ConA | Canavaline | Val(V) | Xie Ansuan |
| ?CY | Ring phosphinylidyne ammonia | P(Ph 3) | Triphenyl phosphorus |
| ?Cys(C) | Halfcystine | HF | Hydrogen fluoride |
| ?DCM | Methylene dichloride | Ts-Cl | Tosyl chloride |
| ?DMF | N, dinethylformamide | RP-HPLC | Reverse high performance liquid chromatography |
| ?TFA | Trifluoracetic acid | TEA | Triethylamine |
| ?EDT | Dithioglycol | TLC | Thin-layer chromatography |
| ?DIEA | Diisopropylethylamine | mPEG-MAL | The mono methoxy polyethylene glycol horse |
| ?BOP | Benzotriazole-1-oxygen-three (two | Glu(E) | L-glutamic acid |
| ?Fmoc | Fluorenylmethyloxycarbonyl | DCC | Dicyclohexylcarbodiimide |
| ?ESI-MS | Electrospray ionization mass spectrum | ELISA MALDI-TOF-MS | The enzyme linked immunological experiment is substance assistant laser desorpted |
The ionization flight time mass spectrum
Among the present invention, all amino acid configurations are the L-type except that being labeled as the D-type.
Embodiment
The following example is represented illustrative embodiment of the present invention, but does not mean that the present invention is subjected to the restriction of this embodiment.
The used solid-phase synthesized carrier Wang resin of embodiment is buied from ACT company, and DCC, HOBt, HBTU, Fmoc protection amino acid is buied by Shanghai gill biochemistry, and TFA is an ACROS company product, and molecular-weight average is that 2000 PEG-OH is a Sigma company product.
Embodiment 1
BocNHCH
2CH
2OCH
2COOH's is synthetic: BocNHCH
2OCH
2COOH
● BocNHCH
2CH
2OH's is synthetic
Water 30ml is added in the 250ml reactor NH
2CH
2CH
2OH6.1g (100mmol) adds in the reactor, is cooled to 0 ℃.Under condition of ice bath, (Boc)
2O21.82g (100mmol) is dissolved in the 30ml dioxane and joins in the reactor, and controlled temperature drips 1mol/LnaOH solution 100ml below 0 ℃, and 40min drips, and rises to room temperature naturally, continues reaction 12 hours, (Boc)
2O disappears, stopped reaction, and the some plate detects, and reaction solution ethyl acetate extraction three times with saturated NaCl solution washing, are used anhydrous Na
2SO
4Drying, evaporated under reduced pressure obtains the 15.6g colorless oil, yield 97.2%.
● BocNHCH
2CH
2OCH
2COOH's is synthetic
In the 500ml there-necked flask, add and heavily steam DMF350ml, BocNH
2CH
2OH10.54g (0.1mol) adds NaH (52%) 8.15g (0.2mol), and no bubble is emerged to the solution, drips BrCH then
2The DMF solution of COOH13.65g (0.15mmol), stirring at room 20 hours is handled, pressure reducing and steaming DMF, with the suitable quantity of water dissolving, with an amount of extracted with diethyl ether twice, water is regulated the pH value between 2-3 with saturated sodium sulfate, with ethyl acetate extraction water three times, use saturated NaCl solution washing then, use anhydrous sodium sulfate drying at last, evaporated under reduced pressure, obtain the 5.51g light yellow oil, yield 38%.
Embodiment 2:
Cys-Glu-Val-Val-Glu-SCH
2CH
2CONH
2Synthetic:
(charge capacity is 0.57mmol/g to the 350mgMBHA resin, 0.2mmol), be suspended among the DMF, add 0.12gHOBt successively, 150 μ L 3-thiohydracrylic acids (1.2mmol), 160mg DCC, add a spot of DCM dissolving fully, at room temperature magnetic agitation was 4 hours, with DMF, DCM, each washed twice of MeOH, DCM, each two minutes.The triketohydrindene hydrate check is negative.Use 50mg acthiol-J hydrochloride (0.2mmol) then; 100mg (0.2mmol) triphenyl phosphorus and 120 μ IDIEA (0.2mmol) mixing are dissolved in DMF; add in the resin after five minutes; room temperature reaction two hours; use DMF; DCM; MeOH; each twice of DCM washing; the amino acid of the BOC protection of 4 times of amounts; BOP; the DIEA of 6 times of amounts mixes; be dissolved in DMF; mixture joins in the reactor after five minutes; room temperature reaction 2 hours; with DMF; DCM; MeOH; the DCM washing; detect with Ellman experiment qualitatively; negative solution resin is colourless or faint yellow; reacted one hour if be orange then reduce by half with above-mentioned condensation dosage again; use BOC/Bzl solid phase condensation system and progressively prolong peptide chain from the C end; with 4NHCl/DIOX (0.05% indoles) deprotection; condensation reaction was reacted 1 hour with the BOC-AA of 2 times of amounts and the DCC/HOBt of 2 times of amounts; per step condensation all detects with the triketohydrindene hydrate experiment; if it is positive then use the BOC-AA of 4 times of amounts again; the DIEA reaction half hour of BOP and 6 times of amounts; after the peptide chain end of synthesis; linear peptides thioesters HF/P-thiocresol/m-cresol (93/2/5; v/v/v); downcut from resin after 1.5 hours 0 ℃ of reaction; HF drains the back and washs for several times with the freezing anhydrous diethyl ether of sodium silk exsiccant; Glacial acetic acid with 10% extracts thick peptide, and freeze-drying is preserved.
Embodiment three: encircle the synthetic of (CEVVE):
(charge capacity is 0.57mmol/g to the 350mgMBHA resin, 0.2mmol), be suspended among the DMF, add 0.12gHOBt successively, 150 μ L 3-thiohydracrylic acids (1.2mmol), 160mg DCC, add a spot of DCM dissolving fully, at room temperature magnetic agitation was 4 hours, with DMF, DCM, each washed twice of MeOH, DCM, each two minutes.The triketohydrindene hydrate check is negative.Use 50mg acthiol-J hydrochloride (0.2mmol) then; 100mg (0.2mmol) triphenyl phosphorus and 120 μ lDIEA (0.2mmol) mixing are dissolved in DMF; add in the resin after five minutes; room temperature reaction two hours; use DMF; DCM; MeOH; each twice of DCM washing; the amino acid of the BOC protection of 4 times of amounts; BOP; the DIEA of 6 times of amounts mixes; be dissolved in DMF; mixture joins in the reactor after five minutes; room temperature reaction 2 hours; with DMF; DCM; MeOH; the DCM washing; detect with Ellman experiment qualitatively; negative solution resin is colourless or faint yellow; reacted one hour if be orange then reduce by half with above-mentioned condensation dosage again; use BOC/BZL solid phase condensation system and progressively prolong peptide chain from the C end; with 4NHCl/DIOX (0.05% indoles) deprotection; condensation reaction was reacted 1 hour with the BOC-AA of 2 times of amounts and the DCC/HOBt of 2 times of amounts; per step condensation all detects with the triketohydrindene hydrate experiment; if it is positive then use the BOC-AA of 4 times of amounts again; the DIEA reaction half hour of BOP and 6 times of amounts; after the peptide chain end of synthesis; linear peptides thioesters HF/P-thiocresol/m-cresol (93/2/5; v/v/v); downcut from resin after 1.5 hours 0 ℃ of reaction; HF drains the back and washs for several times with the freezing anhydrous diethyl ether of sodium silk exsiccant; Glacial acetic acid with 10% extracts thick peptide, and freeze-drying is preserved.Also the buffered soln of cyclization directly can be extracted the linear peptides thioesters and carry out ring-closure reaction.If peptide thioesters solubleness is bad, it is also conceivable that and use CH
3CN/H
2O extracts thick peptide, and CH is taken out in decompression then
3Freeze-drying is preserved behind the CN.
The linear peptides thioesters carries out ring-closure reaction after with gel filtration chromatography preliminary purification or HPLC purifying, be reflected at NaHCO
3The aqueous solution in carry out, can suitably add CH if solubleness is bad
3The concentration of CN, control pH value adds the oxidation that TCEP prevents sulfydryl at 7.3-7.6, and reaction is reflected in 4 hours and is finished by the HPLC monitoring, and product is identified with ESI-MS.
Embodiment four: (CKEVVEE's is synthetic for the PEG-MAL-ring
1 mPEG
5000-MAL's is synthetic
Weighing m PEG
5000-OH 20g (4mmol) places the 250ml reaction flask, adds 100mlCH
2Cl
2, add 3.0ml Et again after the solid dissolving
3N (20mmmol) and 3.8g Ts-Cl (20mmol), the stirring at room reaction.TLC (CH
3OH: CH
2Cl
2=1: 6) monitoring reaction fully after, rotary evaporation removes and desolvates, and adds the 100ml anhydrous diethyl ether and is settled out solid, uses dehydrated alcohol recrystallization twice again, 15.2g mPEG
5000-OTs, yield 70%.
With 15g mPEG
5000-OTs (3mmol) is dissolved in 30ml DMF, adds 1.68g (18mmol) potassium phthalimide, at N
2Under the protection, 120 ℃ were reacted 4 hours.Subtract with boiling off solvent, resistates is dissolved in the 50ml dehydrated alcohol, add the 2.0ml hydrazine hydrate, back flow reaction 4 hours.Rotary evaporation removes and desolvates, and resistates is dissolved in CH
2Cl
2, remove by filter insolubles, the filtrate rotary evaporation is removed desolvate again, be settled out solid with anhydrous diethyl ether, again with dehydrated alcohol-ether recrystallization, get 12.5g mPEG
5000-NH
2, yield 83%.
With 1.25g mPEG
5000-NH
2Be dissolved in the 10ml dioxane, add maleic anhydride 0.1g, 80C stirring reaction 30min.The pressure reducing and steaming solvent adds the 50ml anhydrous diethyl ether, and cooling is settled out solid, and filter collection solid gets 1.10g after the drying.The gained solid is dissolved in the 15ml diacetyl oxide, adds the 0.5g sodium acetate, 100 ℃ of stirring reaction 45min.The pressure reducing and steaming solvent dissolves resistates with methylene dichloride, the elimination insolubles adds proper amount of active carbon in filtrate, place 30min, the filtering gac is concentrated into filtrate dried, add anhydrous diethyl ether, be settled out polity, get light yellow solid 0.61g mPEG after filter collection, the drying
5000-MAL, yield 48%.RP-HPLC analyzes: t
R=36.79min.
Chromatographic condition: Waters 600 HPLC
Chromatographic column: Inersil ODS-3 (10 * 250mm) ultraviolet detection wavelength: 215nm
Moving phase: A-0.05%TFA/H
2O B-0.05%TFA/70%CH
3CN/H
2O
Flow velocity: 2.0mL/min
| Gradient (linearity): | t(min) | A％ | B％ |
| 0 5 35 40 45 | 100 100 0 0 100 | 0 0 100 100 0 |
(charge capacity is 0.57mmol/g to the 350mgMBHA resin, 0.2mmol), be suspended among the DMF, add 0.12gHOBt successively, 150 μ L 3-thiohydracrylic acids (1.2mmol), 160mg DCC, add a spot of DCM dissolving fully, at room temperature magnetic agitation was 4 hours, with DMF, DCM, each washed twice of MeOH, DCM, each two minutes.The triketohydrindene hydrate check is negative.Use 50mg acthiol-J hydrochloride (0.2mmol) then; 100mg (0.2mmol) triphenyl phosphorus and 120 μ lDIEA (0.2mmol) mixing are dissolved in DMF; add in the resin after five minutes; room temperature reaction two hours; use DMF; DCM; MeOH; each twice of DCM washing; the amino acid of the BOC protection of 4 times of amounts; BOP; the DIEA of 6 times of amounts mixes; be dissolved in DMF; mixture joins in the reactor after five minutes; room temperature reaction 2 hours; with DMF; DCM; MeOH; the DCM washing; detect with Ellman experiment qualitatively; negative solution resin is colourless or faint yellow; reacted one hour if be orange then reduce by half with above-mentioned condensation dosage again; use BOC/Bzl solid phase condensation system and progressively prolong peptide chain from the C end; with 4NHCl/DIOX (0.05% indoles) deprotection; condensation reaction was reacted 1 hour with the BOC-AA of 2 times of amounts and the DCC/HOBt of 2 times of amounts; per step condensation all detects with the triketohydrindene hydrate experiment; if it is positive then use the BOC-AA of 4 times of amounts again; the DIEA reaction half hour of BOP and 6 times of amounts; after the peptide chain end of synthesis; linear peptides thioesters HF/P-thiocresol/m-cresol (93/2/5; v/v/v); downcut from resin after 1.5 hours 0 ℃ of reaction; HF drains the back and washs for several times with the freezing anhydrous diethyl ether of sodium silk exsiccant; Glacial acetic acid with 10% extracts thick peptide, and freeze-drying is preserved.
2, ring (CEVVE) is synthetic:
(charge capacity is 0.57mmol/g to the 350mgMBHA resin, 0.2mmol), be suspended among the DMF, add 0.12gHOBt successively, 150 μ L 3-thiohydracrylic acids (1.2mmol), 160mg DCC, add a spot of DCM dissolving fully, at room temperature magnetic agitation was 4 hours, with DMF, DCM, each washed twice of MeOH, DCM, each two minutes.The triketohydrindene hydrate check is negative.Use 50mg acthiol-J hydrochloride (0.2mmol) then; 100mg (0.2mmol) triphenyl phosphorus and 120 μ lDIEA (0.2mmol) mixing are dissolved in DMF; add in the resin after five minutes; room temperature reaction two hours; use DMF; DCM; MeOH; each twice of DCM washing; the amino acid of the BOC protection of 4 times of amounts; BOP; the DIEA of 6 times of amounts mixes; be dissolved in DMF; mixture joins in the reactor after five minutes; room temperature reaction 2 hours; with DMF; DCM; MeOH; the DCM washing; detect with Ellman experiment qualitatively; negative solution resin is colourless or faint yellow; reacted one hour if be orange then reduce by half with above-mentioned condensation dosage again; use BOC/BZL solid phase condensation system and progressively prolong peptide chain from the C end; with 4NHCl/DIOX (0.05% indoles) deprotection; condensation reaction was reacted 1 hour with the BOC-AA of 2 times of amounts and the DCC/HOBt of 2 times of amounts; per step condensation all detects with the triketohydrindene hydrate experiment; if it is positive then use the BOC-AA of 4 times of amounts again; the DIEA reaction half hour of BOP and 6 times of amounts; after the peptide chain end of synthesis; linear peptides thioesters HF/P-thiocresol/m-cresol (93/2/5; v/v/v); downcut from resin after 1.5 hours 0 ℃ of reaction; HF drains the back and washs for several times with the freezing anhydrous diethyl ether of sodium silk exsiccant; Glacial acetic acid with 10% extracts thick peptide, and freeze-drying is preserved.Also the buffered soln of cyclization directly can be extracted the linear peptides thioesters and carry out ring-closure reaction.If peptide thioesters solubleness is bad, it is also conceivable that and use CH
3CN/H
2O extracts thick peptide, and CH is taken out in decompression then
3Freeze-drying is preserved behind the CN.
The linear peptides thioesters carries out ring-closure reaction after with gel filtration chromatography preliminary purification or HPLC purifying, be reflected at NaHCO
3The aqueous solution in carry out, can suitably add CH if solubleness is bad
3The concentration of CN, control pH value adds the oxidation that TCEP prevents sulfydryl at 7.3-7.6, and reaction is reflected in 4 hours and is finished by the HPLC monitoring, and product is identified with ESI-MS.
3, the PEG-MAL of cyclic peptide modifies
Will be soluble in water through the ring behind the RP-HPLC purifying (CEVVE), transfer pH to 8 with sodium bicarbonate, add 3 times of normal mPEG
5000-MAL, room temperature reaction, with RP-HPLC monitoring reaction process and separated product, reaction was generally finished in four hours.Cys (mPEG
5000-MAL)-T α
1(17-24) analyze through MALDI-TOF-MS, a series of peaks are arranged near 6173, it is about 44 that adjacent two peak molecular weight differ, and has the typical structure feature of polyoxyethylene glycol.By with the mPEG-NH that does not connect the cyclic peptide molecule
2Relatively, deduct the formula weight as the maleoyl imido of activation functional group, the molecular weight of its value fundamental sum cyclic peptide is corresponding, proves the mPEGization modification that has successfully realized the cyclic peptide compound.
Embodiment 5:
3The H-tdR method of mixing detects the increment reaction to mouse spleen lymphocyte:
The preparation of splenocyte suspension: aseptic taking-up spleen, with frosted glass plate mouse spleen is ground, make splenocyte suspension.After the splitting erythrocyte, wash three times counting (viable cell is more than 95%).With the RPMI1640 nutrient solution that contains 10%FBS splenocyte concentration is adjusted to 4 * 10
6Cell/ml.This experiment adds ConA (concanavalin A) 5ug/ml inducer T lymphocyte propagation.With
3H-TdR mixes the propagation that standard measure is measured cell.At 37 ℃, 5%CO
2Cultivated 48 hours in the incubator.Before finish cultivating 7-8 hour, every hole added 25 μ l
3The H-thymidylic acid (contains 2 * 10
4Bq).After cultivate finishing, with the cell harvesting instrument (HARVESTER, TOMTEC) collecting cell on glass fibre membrane, with liquid dodge the numeration instrument (MicroBeta Trilux, PerkinElmer) detect [
3H]-incorporation of thymidine in DNA, represent the cell proliferation situation with the cpm value.Concrete detected result is referring to table 1.
Result evaluation: proliferation of lymphocytes adopts detected sample cpm value to deduct positive control sample cpm value, removes positive control sample cpm value then, be labeled as+strengthen/-% of inhibition.In view of specimen does not have the non-specific cytotoxicity effect, result queue is+(enhancing)/-more than 15% of (inhibition) (common during more than 10% also can) according to the P value, just represent that sample has activity.
Table 1 T α
1And the T lymphproliferation response result of analogue
| Measure concentration | The T lymphocyte | T cell proliferation | Active result | ||
| The sample name | Con A stimulates | Comprehensive activity assessment | |||
| ug/ml | CPM mean value | SD | The P value | ||
| Contrast | 28659 | 420 | |||
| CKEVVEKEVVE | 1 | 25205 | 1864 | 0.0784 | -12.05％ |
| 10 | 28512 | 524 | 0.7245 | -0.05％ | |
| 100 | 41342 | 2942 | 0.0159 | 44.26％ | |
| CKEVVEEA | 1 | 29405 | 2950 | 0.7055 | 2.60％ |
| 10 | 30715 | 2841 | 0.3362 | 7.17％ | |
| 100 | 61281 | 2531 | 0.0016 | 113.83％ | |
| Ring (CKEVVEEAE) | 1 | 27561 | 1113 | 0.2233 | -3.83％ |
| 10 | 32792 | 424 | 0.0003 | 14.42％ | |
| 100 | 61476 | 122 | 0.0000 | 114.51％ | |
| Ring (CKEVVE) | 1 | 28143 | 1633 | 0.6434 | -1.80％ |
| 10 | 34065 | 1427 | 0.0162 | 18.86％ | |
| 100 | 61766 | 5163 | 0.0077 | 115.52％ | |
| Ring (CEVVE) | 1 | 30065 | 2055 | 0.3576 | 4.90％ |
| 10 | 33462 | 3431 | 0.1342 | 16.76％ | |
| 100 | 58669 | 1059 | 0.0001 | 104.71％ | |
| Ring (CKEVVEEA) | 1 | 27000 | 2980 | 0.4371 | -5.79％ |
| 10 | 32206 | 2111 | 0.0954 | 12.38％ | |
| 100 | 53927 | 5412 | 0.0145 | 88.17％ | |
| Ring (CLKEVVE) | 1 | 21205 | 897 | 0.0013 | -26.01％ |
| 10 | 47060 | 529 | 0.0000 | 64.21％ | |
| 100 | 57103 | 1733 | 0.0007 | 99.25％ | |
| Ring (CKEVVEKEVVE) | 1 | 27461 | 831 | 0.1135 | -4.18％ |
| 10 | 31907 | 967 | 0.0164 | 11.33％ | |
| 100 | 44826 | 1871 | 0.0031 | 56.41％ | |
| Ring (CKEVVEE) | 1 | 29557 | 1574 | 0.4293 | 3.13％ |
| 10 | 34137 | 737 | 0.0012 | 19.11％ | |
| 100 | 37684 | 1990 | 0.0129 | 31.49％ |
The cpm value is represented the cell proliferation situation, and SD is the standard deviation of data, and this carries out the probability that indifference is arranged of statistical study P value representation experimental data and ConA control group data, between P＜two groups of data of 0.05 expression significant difference is arranged.L＝-NHCH
2CH
2OCH
2COOH-
Claims (19)
1, tetrapeptide to ten peptide derivant and steric isomer thereof, it is the compound of (I) group:
X
1-Y
1-Y
2-X
2
X
1-X
2-Y
1-Y
2-X
3
X
1-X
2-X
3-Y
1-Y
2-X
4
X
1-X
2-Y
1-Y
2-X
3-X
4
X
1-X
2-X
3-Y
1-Y
2-X
4-X
5
X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3
X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3
X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5
X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6
X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4
X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4
X
1-X
2-X
3-X
4-Y
1-Y
2-X
5
X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6
X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7
X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7
X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7 (I)
Wherein, X
1, X
2, X
3, X
4, X
5, X
6, X
7Be natural or non-natural alkalescence, acidity or the aromatic amino acid and the derivative thereof of L-or D-type independently, described basic aminoacids is selected from Arg, Lys, Glu, Cys, His, Trp, Mob, Nal, Pya, Phe (X) and Phg (X), wherein X is optional single the replacement or two replacements of hydrogen, halogen, nitro, carboxyl or C1-C4 alkyl, and substituting group is selected from H, 4-F, 3-F, 2-F, 4-Cl, 2-Cl, 4-Br, 2-Br, 3-Br, 2,5-2Cl, 4-F, 3-Cl, 3-NO
2Acidic amino acid is selected from: Asp, Glu, His, Tyr, Trp, Mob, Nal, Pya and Phg (X), wherein X is optional single the replacement or two replacements of hydrogen, halogen, nitro, carboxyl or C1-C4 alkyl, and substituting group is selected from H, 4-F, 3-F, 2-F, 4-Cl, 2-Cl, 4-Br, 2-Br, 3-Br, 2,5-2Cl, 4-F, 3-Cl, 3-NO
2
Y
1, Y
2, Y
3, Y
4Independently be that the natural or non-natural of L-or D-type is neutral, lipotropy or aromatic amino acid and derivative thereof, be selected from Gly, Ala, β-Ala, GABA, Val, Leu, Ile, Pro, His, Tyr, Typ, Mob, Nal, Pya, Phe (X), Phg (X), wherein X is optional single the replacement or two replacements of hydrogen, halogen, nitro, carboxyl or C1-C4 alkyl, and substituting group is selected from H, 4-F, 3-F, 2-F, 4-Cl, 2-Cl, 4-Br, 2-Br, 3-Br, 2,5-2Cl, 4-F, 3-Cl, 3-NO
2
2, described tetrapeptide to ten peptide derivant of claim 1 and steric isomer thereof, wherein the amino in site is modified to the compound shown in following (II) group through PEG arbitrarily, and wherein said amino comprises the amino and amino acid side chain amino of N-end:
[PEG-X-(CH
2)
MCO-NH]
z-X
1-Y
1-Y
2-X
2
[PEG-X-(CH
2)
MCO-NH]
z-X
1-X
2-Y
1-Y
2-X
3
[PEG-X-(CH
2)
MCO-NH]
z-X
1-X
2-X
3-Y
1-Y
2-X
4
[PEG-X-(CH
2)
MCO-NH]
z-X
1-X
2-Y
1-Y
2-X
3-X
4
[PEG-X-(CH
2)
MCO-NH]
z-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5
[PEG-X-(CH
2)
MCO-NH]
z-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3
[PEG-X-(CH
2)
MCO-NH]
z-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3
[PEG-X-(CH
2)
MCO-NH]
z-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5
[PEG-X-(CH
2)
MCO-NH]
z-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6
[PEG-X-(CH
2)
MCO-NH]
z-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4
[PEG-X-(CH
2)
MCO-NH]
z-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4
[PEG-X-(CH
2)
MCO-NH]
z-X
1-X
2-X
3-X
4-Y
1-Y
2-X
5
[PEG-X-(CH
2)
MCO-NH]
z-X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6
[PEG-X-(CH
2)
MCO-NH]
z-X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7
[PEG-X-(CH
2)
MCO-NH]
z-X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7
[PEG-X-(CH
2)
MCO-NH]
z-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7(II)
Wherein PEG represents: RO (CH
2CH
2O)
n-CH
2CH
2, R=H or C and CH
3, n=5-1000 wherein; X=O, NH or NHCO; M=0-6; Z=1-3, X
1, X
2, X
3, X
4, X
5, X
6, X
7, Y
1, Y
2, Y
3, Y
4Definition shown in claim 1.
3, described tetrapeptide to ten peptide derivant of claim 1 and steric isomer thereof, wherein the carboxyl in site is the compound that (III) as follows organizes through the PEG covalent modification arbitrarily, wherein said carboxyl comprises C-end carboxyl, aspartic acid and L-glutamic acid side chain carboxyl group:
[PEG-X-CO]
z-X
1-Y
1-Y
2-X
2
[PEG-X-CO]
z-X
1-X
2-Y
1-Y
2-X
3
[PEG-X-CO]
z-X
1-X
2-X
3-Y
1-Y
2-X
4
[PEG-X-CO]
z-X
1-X
2-Y
1-Y
2-X
3-X
4
[PEG-X-CO]
z-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5
[PEG-X-CO]
z-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3
[PEG-X-CO]
z-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3
[PEG-X-CO]
z-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5
[PEG-X-CO]
z-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6
[PEG-X-CO]
z-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4
[PEG-X-CO]
z-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4
[PEG-X-CO]
z-X
1-X
2-X
3-X
4-Y
1-Y
2-X
5
[PEG-X-CO]
z-X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6
[PEG-X-CO]
z-X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7
[PEG-X-CO]
z-X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7
[PEG-X-CO]
z-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7 (III)
X wherein
1, X
2, Y
1, Y
2, X
3, X
4, X
5, X
6, X
7, Y
1, Y
2, Y
3, Y
4Definition shown in claim 1, X=O or NH, Z=1-3.
4. described tetrapeptide to ten peptide derivant of claim 1 and steric isomer thereof, optional position in peptide sequence wherein comprises introducing in N end and C end and the peptide fragment forming the compound that (IV) as follows organizes behind the halfcystine:
Cys-X
1-Y
1-Y
2-X
2
Cys-X
1-X
2-Y
1-Y
2-X
3
Cys-X
1-X
2-X
3-Y
1-Y
2-X
4
Cys-X
1-X
2-Y
1-Y
2-X
3-X
4
Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5
Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3
Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3
Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5
Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6
Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4
Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4
Cys-X
1-X
2-X
3-X
4-Y
1-Y
2-X
5
Cys-X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6
Cys-X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7
Cys-X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7
Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7 (IV)
5, described tetrapeptide to ten peptide derivant of claim 4 and steric isomer thereof, it is further modified the back through the method that is selected from PEG-MAL, PEG-VS and PEG-IODS and forms the compound that (V) as follows organizes, and wherein PEG can be chain, starlike, ring-type, multi-arm type structure:
PEG-M-Cys-X
1-Y
1-Y
2-X
2
PEG-M-Cys-X
1-X
2-Y
1-Y
2-X
3
PEG-M-Cys-X
1-X
2-X
3-Y
1-Y
2-X
4
PEG-M-Cys-X
1-X
2-Y
1-Y
2-X
3-X
4
PEG-M-Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5
PEG-M-Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3
PEG-M-Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3
PEG-M-Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5
PEG-M-Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6
PEG-M-Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4
PEG-M-Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4
PEG-M-Cys-X
1-X
2-X
3-X
4-Y
1-Y
2-X
5
PEG-M-Cys-X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6
PEG-M-Cys-X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7
PEG-M-Cys-X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7
PEG-M-Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7(V), wherein
Cys is a halfcystine, links to each other with M group covalency by the side chain sulphur atom; X
1, X
2, Y
1, Y
2, X
3, X
4, X
5, X
6, X
7, Y
1, Y
2, Y
3, Y
4Definition shown in claim 1.
6, described tetrapeptide to ten peptide derivant of claim 1 and steric isomer thereof, wherein introduce Electron Affinities group or nucleophilic group at the C end, and it is corresponding to opposite nucleophilic group or the Electron Affinities group of N end introducing, obtain the compound of (VI) group as follows, wherein said nucleophilic reagent is selected from the iodine negative ion, water, the hydroxyl negative ion, the methoxyl group negative ion, the ethanoyl negative ion, amino, the nitrate radical negative ion, the nitrite anions negative ion, the azido-negative ion, the cyano group negative ion, 1-proyl negative ion, the dimethyl malonate negative ion, the sulfydryl negative ion, the methylthio group negative ion, the thiocyanogen negative ion, dimethyl sulphide, front three phosphorus; Described electrophilic reagent is selected from thiocarboxyl group acetyl ammonia, halogen, mineral acid, organic acid, aldehyde, active ketone, carboxylic acid, ester, nitro-compound:
Z
1-X
1-Y
1-Y
2-X
2-Z
2
Z
1-X
1-X
2-Y
1-Y
2-X
3-Z
2
Z
1-X
1-X
2-X
3-Y
1-Y
2-X
4-Z
2
Z
1-X
1-X
2-Y
1-Y
2-X
3-X
4-Z
2
Z
1-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Z
2
Z
1-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-Z
2
Z
1-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4-Z
2
Z
1-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4-Z
2
Z
1-X
1-X
2-X
3-X
4-Y
1-Y
2-X
5-Z
2
Z
1-X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6-Z
2
Z
1-X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7-Z
2
Z
1-X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7-Z
2
Z
1-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7-Z
2 (VI)，
Z wherein
1And Z
2Be one group of amino-acid residue or other fragment, work as Z with nucleophilic group and Electron Affinities group
1Z when having nucleophilic group
2Have the Electron Affinities group, work as Z
1Z when having the Electron Affinities group
2Have nucleophilic group.
7, described tetrapeptide to ten peptide derivant of claim 6 and steric isomer thereof, it is:
CEVVE-SCH
2CH
2CONH
2
CKEVVE-SCH
2CH
2CONH
2
CKKEVVE-SCH
2CH
2CONH
2
CKEVVEE-SCH
2CH
2CONH
2
CEKKEVVE-SCH
2CH
2CONH
2
CKEKKEVVE-SCH
2CH
2CONH
2
CKEVVEKEVVE-SCH
2CH
2CONH
2
CKEVVEEAE-SCH
2CH
2CONH
2
CKEVVEEA-SCH
2CH
2CONH
2, or
CKEVVEEAEN-SCH
2CH
2CONH
2。
8, claim 4 or 6 described tetrapeptide to ten peptide derivant and steric isomers thereof, wherein (IV) and (VI) any site of the compound of group introduce aliphatic chain, aliphatic ether chain, thioether chain, amino acid and other flexible chain-like structure unit, obtain the compound of (VII) group as follows:
Cys-L
n-X
1-Y
1-Y
2-X
2
Cys-L
n-X
1-X
2-Y
1-Y
2-X
3
Cys-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4
Cys-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4
Cys-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5
Cys-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3
Cys-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3
Cys-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5
Cys-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6
Cys-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4
Cys-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4
Cys-L
n-X
1-X
2-X
3-X
4-Y
1-Y
2-X
5
Cys-L
n-X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6
Cys-L
n-X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7
Cys-L
n-X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7
Cys-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7，
Or following structure:
Z
1-L
n-X
1-Y
1-Y
2-X
2-Z
2
Z
1-L
n-X
1-X
2-Y
1-Y
2-X
3-Z
2
Z
1-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-Z
2
Z
1-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4-Z
2
Z
1-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Z
2
Z
1-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-Z
2
Z
1-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4-Z
2
Z
1-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4-Z
2
Z
1-L
n-X
1-X
2-X
3-X
4-Y
1-Y
2-X
5-Z
2
Z
1-L
n-X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6-Z
2
Z
1-L
n-X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7-Z
2
Z
1-X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7-Z
2
Z
1-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7-Z
2 (VII)
Wherein, L represents the chain-like structure unit of any flexibility, n=1-4, the site, L place shown in the above general formula is not the unique site that can introduce, L can be in peptide sequence the optional position except that two ends.
9, described tetrapeptide to ten peptide derivant of claim 8 and steric isomer thereof, it comprises:
CLEVVE
CLKEVVE
CLKKEVVE
CLKEVVEE
CLEKKEVVE
CLKEKKEVVE
CLKEVVEKEVVE
CLKEVVEEAE
CLKEVVEEA
CLKEVVEEAEN
CLLEVVE
CLLKEVVE
CLLKKEVVE
CLLKEVVEE
CLLEKKEVVE
CLLKEKKEVVE
CLLKEVVEKEVVE
CLLKEVVEEAE
CLLKEVVEEA
CLLKEVVEEAEN，
Or the compound of following structure:
CLEVVE-SCH
2CH
2CONH
2
CLKEVVE-SCH
2CH
2CONH
2
CLKKEVVE-SCH
2CH
2CONH
2
CLKEVVEE-SCH
2CH
2CONH
2
CLEKKEVVE-SCH
2CH
2CONH
2
CLKEKKEVVE-SCH
2CH
2CONH
2
CLKEVVEKEVVE-SCH
2CH
2CONH
2
CLKEVVEEAE-SCH
2CH
2CONH
2
CLKEVVEEA-SCH
2CH
2CONH
2
CLKEVVEEAEN-SCH
2CH
2CONH
2
CLLEVVE-SCH
2CH
2CONH
2
CLLKEVVE-SCH
2CH
2CONH
2
CLLKKEVVE-SCH
2CH
2CONH
2
CLLKEVVEE-SCH
2CH
2CONH
2
CLLEKKEVVE-SCH
2CH
2CONH
2
CLLKEKKEVVE-SCH
2CH
2CONH
2
CLLKEVVEKEVVE-SCH
2CH
2CONH
2
CLLKEVVEEAE-SCH
2CH
2CONH
2
CLLKEVVEEA-SCH
2CH
2CONH
2
CLLKEVVEEAEN-SCH
2CH
2CONH
2，
Wherein, L=-NHCH
2CH
2OCH
2COO-.
10, claim 1,4 or 8 described tetrapeptide to ten peptide derivant and steric isomers thereof, the compound of wherein arbitrary described (I), (IV), (VII) group carries out cyclization with any known cyclization method, obtains the ring compound shown in (VIII) group:
Ring (X
1-Y
1-Y
2-X
2)
Ring (X
1-X
2-Y
1-Y
2-X
3)
Ring (X
1-X
2-X
3-Y
1-Y
2-X
4)
Ring (X
1-X
2-Y
1-Y
2-X
3-X
4)
Ring (X
1-X
2-X
3-Y
1-Y
2-X
4-X
5)
Ring (X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3)
Ring (X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3)
Ring (X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5)
Ring (X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6)
Ring (X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4)
Ring (X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4)
Ring (X
1-X
2-X
3-X
4-Y
1-Y
2-X
5)
Ring (X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6)
Ring (X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7)
Ring (X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7)
Ring (X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7)
Or following structure:
Ring (Cys-X
1-Y
1-Y
2-X
2)
Ring (Cys-X
1-X
2-Y
1-Y
2-X
3)
Ring (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4)
Ring (Cys-X
1-X
2-Y
1-Y
2-X
3-X
4)
Ring (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5)
Ring (Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3)
Ring (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3)
Ring (Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5)
Ring (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6)
Ring (Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4)
Ring (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4)
Ring (Cys-X
1-X
2-X
3-X
4-Y
1-Y
2-X
5)
Ring (Cys-X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6)
Ring (Cys-X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7)
Ring (Cys-X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7)
Or following compound:
Ring (Z
1-L
n-X
1-Y
1-Y
2-X
2)
Ring (Z
1-L
n-X
1-X
2-Y
1-Y
2-X
3)
Ring (Z
1-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4)
Ring (Z
1-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4)
Ring (Z
1-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5)
Ring (Z
1-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3)
Ring (Z
1-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4)
Ring (Z
1-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4)
Ring (Z
1-L
n-X
1-X
2-X
3-X
4-Y
1-Y
2-X
5)
Ring (Z
1-L
n-X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6)
Ring (Z
1-L
n-X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7)
Ring (Z
1-L
n-X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7)
Ring (Z
1-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7) (VIII)
Wherein, X
1, X
2, Y
1, Y
2, X
3, X
4, X
5, X
6, X
7, Y
1, Y
2, Y
3, Y
4Definition shown in claim 1, Z
1Definition shown in claim 6, L
nDefinition shown in claim 8.
11, described tetrapeptide to ten peptide derivant of claim 10 and steric isomer thereof, wherein said compound is following structure:
Ring (EVVE)
Ring (KEVVE)
Ring (KKEVVE)
Ring (KEVVEE)
Ring (EKKEVVE)
Ring (KEKKEVVE)
Ring (KEVVEKEVVE)
Ring (KEVVEEAE)
Ring (KEVVEEA)
Ring (KEVVEEAEN)
Or
Ring (CEVVE)
Ring (CKEVVE)
Ring (CKKEVVE)
Ring (CKEVVEE)
Ring (CEKKEVVE)
Ring (CKEKKEVVE)
Ring (CKEVVEKEVVE)
Ring (CKEVVEEAE)
Ring (CKEVVEEA)
Ring (CKEVVEEAEN)
Or:
Ring (CLEVVE)
Ring (CLKEVVE)
Ring (CLKKEVVE)
Ring (CLKEVVEE)
Ring (CLEKKEVVE)
Ring (CLKEKKEVVE)
Ring (CLKEVVEKEVVE)
Ring (CLKEVVEEAE)
Ring (CLKEVVEEA)
Ring (CLKEVVEEAEN)
Or:
Ring (CLLEVVE)
Ring (CLLKEVVE)
Ring (CLLKKEVVE)
Ring (CLLKEVVEE)
Ring (CLLEKKEVVE)
Ring (CLLKEKKEVVE)
Ring (CLLKEVVEKEVVE)
Ring (CLLKEVVEEAE)
Ring (CLLKEVVEEA)
Ring (CLLKEVVEEAEN).
12, described tetrapeptide to ten peptide derivant of claim 10 and steric isomer thereof, the amino in any site is modified through PEG in the compound of wherein said (VIII) group, obtain the compound of (XI) as follows group, wherein said amino comprises the side chain amino of N-end amino and natural amino acid or alpha-non-natural amino acid
[PEG-X-(CH
2)
MCO-NH]
z-ring (X
1-Y
1-Y
2-X
2)
[PEG-X-(CH
2)
MCO-NH]
z-ring (X
1-X
2-Y
1-Y
2-X
3)
[PEG-X-(CH
2)
MCO-NH]
z-ring (X
1-X
2-X
3-Y
1-Y
2-X
4)
[PEG-X-(CH
2)
MCO-NH]
z-ring (X
1-X
2-Y
1-Y
2-X
3-X
4)
[PEG-X-(CH
2)
MCO-NH]
z-ring (X
1-X
2-X
3-Y
1-Y
2-X
4-X
5)
[PEG-X-(CH
2)
MCO-NH]
z-ring (X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3)
[PEG-X-(CH
2)
MCO-NH]
z-ring (X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3)
[PEG-X-(CH
2)
MCO-NH]
z-ring (X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5)
[PEG-X-(CH
2)
MCO-NH]
z-ring (X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6)
[PEG-X-(CH
2)
MCO-NH]
z-ring (X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4)
[PEG-X-(CH
2)
MCO-NH]
z-ring (X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4)
[PEG-X-(CH
2)
MCO-NH]
z-ring (X
1-X
2-X
3-X
4-Y
1-Y
2-X
5)
[PEG-X-(CH
2)
MCO-NH]
z-ring (X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6)
[PEG-X-(CH
2)
MCO-NH]
z-ring (X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7)
[PEG-X-(CH
2)
MCO-NH]
z-ring (X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7)
[PEG-X-(CH
2)
MCO-NH]
z-ring (X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-X
6-Y3-Y4-X
7)
[PEG-X-(CH
2)
MCO-NH]
z-ring (Cys-X
1-Y
1-Y
2-X
2)
[PEG-X-(CH
2)
MCO-NH]
z-ring (Cys-X
1-X
2-Y
1-Y
2-X
3)
[PEG-X-(CH
2)
MCO-NH]
z-ring (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4)
[PEG-X-(CH
2)
MCO-NH]
z-ring (Cys-X
1-X
2-Y
1-Y
2-X
3-X
4)
[PEG-X-(CH
2)
MCO-NH]
z-ring (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5)
[PEG-X-(CH
2)
MCO-NH]
z-ring (Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3)
[PEG-X-(CH
2)
MCO-NH]
z-ring (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3)
[PEG-X-(CH
2)
MCO-NH]
z-ring (Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5)
[PEG-X-(CH
2)
MCO-NH]
z-ring (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6)
[PEG-X-(CH
2)
MCO-NH]
z-ring (Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4)
[PEG-X-(CH
2)
MCO-NH]
z-ring (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4)
[PEG-X-(CH
2)
MCO-NH]
z-ring (Cys-X
1-X
2-X
3-X
4-Y
1-Y
2-X
5)
[PEG-X-(CH
2)
MCO-NH]
z-ring (Cys-X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6)
[PEG-X-(CH
2)
MCO-NH]
z-ring (Cys-X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7)
[PEG-X-(CH
2)
MCO-NH]
z-ring (Cys-X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7)
Or:
[PEG-X-(CH
2)
MCO-NH]
z-ring (Z
1-L
n-X
1-Y
1-Y
2-X
2)
[PEG-X-(CH
2)
MCO-NH]
z-ring (Z
1-L
n-X
1-X
2-Y
1-Y
2-X
3)
[PEG-X-(CH
2)
MCO-NH]
z-ring (Z
1-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4)
[PEG-X-(CH
2)
MCO-NH]
z-ring (Z
1-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4)
[PEG-X-(CH
2)
MCO-NH]
z-ring (Z
1-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5)
[PEG-X-(CH
2)
MCO-NH]
z-ring (Z
1-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3)
[PEG-X-(CH
2)
MCO-NH]
z-ring (Z
1-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4)
[PEG-X-(CH
2)
MCO-NH]
z-ring (Z
1-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4)
[PEG-X-(CH
2)
MCO-NH]
z-ring (Z
1-L
n-X
1-X
2-X
3-X
4-Y
1-Y
2-X
5)
[PEG-X-(CH
2)
MCO-NH]
z-ring (Z
1-L
n-X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6)
[PEG-X-(CH
2)
MCO-NH]
z-ring (Z
1-L
n-X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7)
[PEG-X-(CH
2)
MCO-NH]
z-ring (Z
1-L
n-X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7)
[PEG-X-(CH
2)
MCO-NH]
z-ring (Z
1-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7) (XI)
Wherein said PEG represents: RO (CH
2CH
2O)
n-CH
2CH
2, R=H or C and CH
3, n=5-1000; X=O, NH or NHCO; M=0-6; Z=1-3, X
1, X
2, Y
1, Y
2, X
3, X
4, X
5, X
6, X
7, Y
1, Y
2, Y
3, Y
4Definition shown in claim 1, Z
1, L
nDefinition shown in claim 10.
13, described tetrapeptide to ten peptide derivant of claim 12 and steric isomer thereof comprise following compound:
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CKEVVE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CKKEVVE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CKEVVEE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CEKKEVVE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CKEKKEVVE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CKEVVEKEVVE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CKEVVEEAE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CKEVVEEA)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CKEVVEEAEN)
Or following structure:
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLKEVVE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLKKEVVE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLKEVVEE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLEKKEVVE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLKEKKEVVE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLKEVVEKEVVE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLKEVVEEAE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLKEVVEEA)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLKEVVEEAEN)
Or the compound of following structure:
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLLKEVVE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLLKKEVVE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLLKEVVEE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLLEKKEVVE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLLKEKKEVVE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLLKEVVEKEVVE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLLKEVVEEAE)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLLKEVVEEA)
PEG-CH
2CH
2-X-(CH
2)
mCO-encircles (CLLKEVVEEAEN)
Wherein, X=O, NH or NHCO; M=0-6.
14, described tetrapeptide to ten peptide derivant of claim 10 and steric isomer thereof, the wherein carboxyl process PEG modification in site arbitrarily in the compound of (VIII) group, obtain the compound shown in following (IX), wherein said amino comprises the side chain carboxyl group of C-end amino and natural amino acid or alpha-non-natural amino acid:
[PEG-X-CO]
z-ring (X
1-Y
1-Y
2-X
2)
[PEG-X-CO]
z-ring (X
1-X
2-Y
1-Y
2-X
3)
[PEG-X-CO]
z-ring (X
1-X
2-X
3-Y
1-Y
2-X
4)
[PEG-X-CO]
z-ring (X
1-X
2-Y
1-Y
2-X
3-X
4)
[PEG-X-CO]
z-ring (X
1-X
2-X
3-Y
1-Y
2-X
4-X
5)
[PEG-X-CO]
z-ring (X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3)
[PEG-X-CO]
z-ring (X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3)
[PEG-X-CO]
z-ring (X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5)
[PEG-X-CO]
z-ring (X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6)
[PEG-X-CO]
z-ring (X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4)
[PEG-X-CO]
z-ring (X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4)
[PEG-X-CO]
z-ring (X
1-X
2-X
3-X
4-Y
1-Y
2-X
5)
[PEG-X-CO]
z-ring (X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6)
[PEG-X-CO]
z-ring (X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7)
[PEG-X-CO]
z-ring (X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7)
[PEG-X-CO]
z-ring (X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-X
6-Y3-Y4-X
7)
[PEG-X-CO]
z-ring (Cys-X
1-Y
1-Y
2-X
2)
[PEG-X-CO]
z-ring (Cys-X
1-X
2-Y
1-Y
2-X
3)
[PEG-X-CO]
z-ring (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4)
[PEG-X-CO]
z-ring (Cys-X
1-X
2-Y
1-Y
2-X
3-X
4)
[PEG-X-CO]
z-ring (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5)
[PEG-X-CO]
z-ring (Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3)
[PEG-X-CO]
z-ring (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3)
[PEG-X-CO]
z-ring (Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5)
[PEG-X-CO]
z-ring (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6)
[PEG-X-CO]
z-ring (Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4)
[PEG-X-CO]
z-ring (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4)
[PEG-X-CO]
z-ring (Cys-X
1-X
2-X
3-X
4-Y
1-Y
2-X
5)
[PEG-X-CO]
z-ring (Cys-X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6)
[PEG-X-CO]
z-ring (Cys-X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7)
[PEG-X-CO]
z-ring (Cys-X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7)
Or following structure:
[PEG-X-CO]
z-ring (Z
1-L
n-X
1-Y
1-Y
2-X
2)
[PEG-X-CO]
z-ring (Z
1-L
n-X
1-X
2-Y
1-Y
2-X
3)
[PEG-X-CO]
z-ring (Z
1-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4)
[PEG-X-CO]
z-ring (Z
1-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4)
[PEG-X-CO]
z-ring (Z
1-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5)
[PEG-X-CO]
z-ring (Z
1-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3)
[PEG-X-CO]
z-ring (Z
1-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4)
[PEG-X-CO]
z-ring (Z
1-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4)
[PEG-X-CO]
z-ring (Z
1-L
n-X
1-X
2-X
3-X
4-Y
1-Y
2-X
5)
[PEG-X-CO]
z-ring (Z
1-L
n-X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6)
[PEG-X-CO]
z-ring (Z
1-L
n-X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7)
[PEG-X-CO]
z-ring (Z
1-X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7)
[PEG-X-CO]
z-ring (Z
1-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-X
6-Y3-Y4-X
7) (IX)
Wherein, X
1, X
2, Y
1, Y
2, X
3, X
4, X
5, X
6, X
7, Y
1, Y
2, Y
3, Y
4Definition shown in claim 1, Z
1, L
nDefinition shown in claim 10; X=O or NH, Z=1-3.
15, described tetrapeptide to ten peptide derivant of claim 14 and steric isomer thereof are selected from:
[PEG-X-CO]
z-ring (EVVE)
[PEG-X-CO]
zRing (KEVVE)
[PEG-X-CO]
zRing (KKEVVE)
[PEG-X-CO]
zRing (KEVVEE)
[PEG-X-CO]
zRing (EKKEVVE)
[PEG-X-CO]
zRing (KEKKEVVE)
[PEG-X-CO]
zRing (KEVVEKEVVE)
[PEG-X-CO]
zRing (KEVVEEAE)
[PEG-X-CO]
zRing (KEVVEEA)
[PEG-X-CO]
zRing (KEVVEEAEN)
[PEG-X-CO]
z-ring (CEVVE)
[PEG-X-CO]
zRing (CKEVVE)
[PEG-X-CO]
zRing (CKKEVVE)
[PEG-X-CO]
zRing (CKEVVEE)
[PEG-X-CO]
zRing (CEKKEVVE)
[PEG-X-CO]
zRing (CKEKKEVVE)
[PEG-X-CO]
zRing (CKEVVEKEVVE)
[PEG-X-CO]
zRing (CKEVVEEAE)
[PEG-X-CO]
zRing (CKEVVEEA)
[PEG-X-CO]
zRing (CKEVVEEAEN)
Or following structure:
[PEG-X-CO]
zRing (CLEVVE)
[PEG-X-CO]
zRing (CLKEVVE)
[PEG-X-CO]
zRing (CLKKEVVE)
[PEG-X-CO]
zRing (CLKEVVEE)
[PEG-X-CO]
zRing (CLEKKEVVE)
[PEG-X-CO]
zRing (CLKEKKEVVE)
[PEG-X-CO]
zRing (CLKEVVEKEVVE)
[PEG-X-CO]
zRing (CLKEVVEEAE)
[PEG-X-CO]
zRing (CLKEVVEEA)
[PEG-X-CO]
zRing (CLKEVVEEAEN)
Or the compound of following structure:
[PEG-X-CO]
zRing (CLLEVVE)
[PEG-X-CO]
zRing (CLLKEVVE)
[PEG-X-CO]
zRing (CLLKKEVVE)
[PEG-X-CO]
zRing (CLLKEVVEE)
[PEG-X-CO]
zRing (CLLEKKEVVE)
[PEG-X-CO]
zRing (CLLKEKKEVVE)
[PEG-X-CO]
zRing (CLLKEVVEKEVVE)
[PEG-X-CO]
zRing (CLLKEVVEEAE)
[PEG-X-CO]
zRing (CLLKEVVEEA)
[PEG-X-CO]
zRing (CLLKEVVEEAEN).
16, described tetrapeptide to ten peptide derivant of claim 10 and steric isomer thereof, after wherein halfcystine is introduced in compound optional position in peptide sequence or existing halfcystine position or sequence of (VIII) group, through being selected from PEG-MAL, the method of PEG-VS and PEG-IODS is modified, obtain the compound of (X) as follows group, wherein PEG can be chain, starlike, ring-type, multi-arm type structure:
PEG-M-encircles (Cys-X
1-Y
1-Y
2-X
2)
PEG-M-encircles (Cys-X
1-X
2-Y
1-Y
2-X
3)
PEG-M-encircles (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4)
PEG-M-encircles (Cys-X
1-X
2-Y
1-Y
2-X
3-X
4)
PEG-M-encircles (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5)
PEG-M-encircles (Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3)
PEG-M-encircles (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3)
PEG-M-encircles (Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5)
PEG-M-encircles (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6)
PEG-M-encircles (Cys-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4)
PEG-M-encircles (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4)
PEG-M-encircles (Cys-X
1-X
2-X
3-X
4-Y
1-Y
2-X
5)
PEG-M-encircles (Cys-X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6)
PEG-M-encircles (Cys-X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7)
PEG-M-encircles (Cys-X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7)
PEG-M-encircles (Cys-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7)
Also can be following structure:
PEG-M-encircles (Cys-L
n-X
1-Y
1-Y
2-X
2)
PEG-M-encircles (Cys-L
n-X
1-X
2-Y
1-Y
2-X
3)
PEG-M-encircles (Cys-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4)
PEG-M-encircles (Cys-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4)
PEG-M-encircles (Cys-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5)
PEG-M-encircles (Cys-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3)
PEG-M-encircles (Cys-L
n-X
1-X
2-Y
1-Y
2-X
3-X
4-Y
3-X
5-Y
4)
PEG-M-encircles (Cys-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-Y
3-X
6-Y
4)
PEG-M-encircles (Cys-L
n-X
1-X
2-X
3-X
4-X
5-X
6-Y
1-Y
2-X
7)
PEG-M-encircles (Cys-X
1-X
2-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7)
PEG-M-encircles (Cys-L
n-X
1-X
2-X
3-Y
1-Y
2-X
4-X
5-X
6-Y
3-Y
4-X
7)
PEG-M-encircles (Cys-L
n-X
1-X
2-X
3-X
4-Y
1-Y
2-X
5)
PEG-M-encircles (Cys-L
n-X
1-X
2-X
3-X
4-X
5-Y
1-Y
2-X
6) (X)
Wherein,
X wherein
1, Z
1Can be halfcystine, link to each other with M group covalency by the side chain sulphur atom; X
1, X
2, Y
1, Y
2, X
3, X
4, X
5, X
6, X
7, Y
1, Y
2, Y
3, Y
4Definition shown in claim 1, Z
1, L
nDefinition shown in claim 11.
17. described tetrapeptide to ten peptide derivant of claim 16 and steric isomer thereof are selected from:
[PEG-M]-ring (CEVVE)
[PEG-M]-ring (CKEVVE)
[PEG-M]-ring (CKKEVVE)
[PEG-M]-ring (CKEVVEE)
[PEG-M]-ring (CEKKEVVE)
[PEG-M]-ring (CKEKKEVVE)
[PEG-M] encircles (CKEVVEKEVVE)
[PEG-M] encircles (CKEVVEEAE)
[PEG-M]-ring (CKEVVEEA)
[PEG-M]-ring (CKEVVEEAEN)
Or following structure:
[PEG-M]-ring (CLEVVE)
[PEG-M]-ring (CLKEVVE)
[PEG-M]-ring (CLKKEVVE)
[PEG-M]-ring (CLKEVVEE)
[PEG-M]-ring (CLEKKEVVE)
[PEG-M]-ring (CLKEKKEVVE)
[PEG-M]-ring (CLKEVVEKEVVE)
[PEG-M]-ring (CLKEVVEEAE)
[PEG-M]-ring (CLKEVVEEA)
[PEG-M]-ring (CLKEVVEEAEN)
Or the compound of following structure:
[PEG-M]-ring (CLLEVVE)
[PEG-M]-ring (CLLKEVVE)
[PEG-M]-ring (CLLKKEVVE)
[PEG-M]-ring (CLLKEVVEE)
[PEG-M] encircles (CLLEKKEVVE)
[PEG-M]-ring (CLLKEKKEVVE)
[PEG-M]-ring (CLLKEVVEKEVVE)
[PEG-M]-ring (CLLKEVVEEAE)
[PEG-M]-ring (CLLKEVVEEA)
[PEG-M]-ring (CLLKEVVEEAEN).
18, be selected from arbitrary compound of described tetrapeptide to ten peptide derivant of claim 1 and steric isomer thereof and the purposes that arbitrary combination is used to prepare the medicine that treats and/or prevents immune deficiency, immunologic hypofunction relative disease thereof.
19. be selected from arbitrary compound of described tetrapeptide to ten peptide derivant of claim 1 and steric isomer thereof and the purposes that arbitrary combination is used to prepare healthcare products and makeup thereof.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2004100964592A CN1781933B (en) | 2004-12-01 | 2004-12-01 | Thymosin alpha 1 active segment cyclicpeptide analogue and its poly glycol derivative |
| CN201110034234.4A CN102174084B (en) | 2004-12-01 | 2004-12-01 | Thymosin α1 active fragments cyclic peptide analogue and polyethylene glycol derivative thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2004100964592A CN1781933B (en) | 2004-12-01 | 2004-12-01 | Thymosin alpha 1 active segment cyclicpeptide analogue and its poly glycol derivative |
Related Child Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110034234.4A Division CN102174084B (en) | 2004-12-01 | 2004-12-01 | Thymosin α1 active fragments cyclic peptide analogue and polyethylene glycol derivative thereof |
| CN201210241191.1A Division CN102746385B (en) | 2004-12-01 | 2004-12-01 | Thymosin alpha 1 active fragment cyclopeptide analogue and polyethylene glycol derivative thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1781933A true CN1781933A (en) | 2006-06-07 |
| CN1781933B CN1781933B (en) | 2011-07-20 |
Family
ID=36772597
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2004100964592A Expired - Fee Related CN1781933B (en) | 2004-12-01 | 2004-12-01 | Thymosin alpha 1 active segment cyclicpeptide analogue and its poly glycol derivative |
| CN201110034234.4A Expired - Fee Related CN102174084B (en) | 2004-12-01 | 2004-12-01 | Thymosin α1 active fragments cyclic peptide analogue and polyethylene glycol derivative thereof |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110034234.4A Expired - Fee Related CN102174084B (en) | 2004-12-01 | 2004-12-01 | Thymosin α1 active fragments cyclic peptide analogue and polyethylene glycol derivative thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (2) | CN1781933B (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008151512A1 (en) * | 2007-06-12 | 2008-12-18 | Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. | Site-specific pegylated linear salmon calcitonin derivatives |
| CN1927879B (en) * | 2006-09-25 | 2010-11-24 | 吉林大学 | Thymopentin active isomer and its application in medicine preparation |
| CN102746385A (en) * | 2004-12-01 | 2012-10-24 | 中国人民解放军军事医学科学院毒物药物研究所 | Thymosin alpha 1 active fragment cyclopeptide analogue and polyethylene glycol derivative thereof |
| CN102796168A (en) * | 2011-05-27 | 2012-11-28 | 首都医科大学 | Compounds with thrombolytic activity and preparation method and application thereof |
| WO2017004811A1 (en) * | 2015-07-08 | 2017-01-12 | 中国食品发酵工业研究院 | Active peptide for inhibiting ampa receptor and preparation method and use thereof |
| CN112315909A (en) * | 2020-11-05 | 2021-02-05 | 南开大学 | A kind of functionalized polymer micelle PM-TLK and its preparation method and application |
| JP2022541240A (en) * | 2019-07-17 | 2022-09-22 | パーシピアド，インコーポレイテッド | Boron-containing RHO kinase inhibitor |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1781933B (en) * | 2004-12-01 | 2011-07-20 | 中国人民解放军军事医学科学院毒物药物研究所 | Thymosin alpha 1 active segment cyclicpeptide analogue and its poly glycol derivative |
| CN111454329A (en) * | 2020-04-07 | 2020-07-28 | 哈尔滨师范大学 | Isoindolinone bridged cyclic nonapeptide with anticancer activity and preparation method thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3100974A1 (en) * | 1980-01-18 | 1982-01-21 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V., 3400 Göttingen | Medicaments having immunoregulating action which contain thymosin alpha 1 fragments, and thymosin alpha 1 fragments |
| US4547489A (en) * | 1984-06-11 | 1985-10-15 | Ortho Pharmaceutical Corporation | Conformationally restricted thymopentin-like compounds |
| CN1532206A (en) * | 2003-03-21 | 2004-09-29 | 中国人民解放军军事医学科学院毒物药 | Active fragment of thymosin alphal and its polyethylene glycol derivatives |
| CN1781933B (en) * | 2004-12-01 | 2011-07-20 | 中国人民解放军军事医学科学院毒物药物研究所 | Thymosin alpha 1 active segment cyclicpeptide analogue and its poly glycol derivative |
-
2004
- 2004-12-01 CN CN2004100964592A patent/CN1781933B/en not_active Expired - Fee Related
- 2004-12-01 CN CN201110034234.4A patent/CN102174084B/en not_active Expired - Fee Related
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102746385A (en) * | 2004-12-01 | 2012-10-24 | 中国人民解放军军事医学科学院毒物药物研究所 | Thymosin alpha 1 active fragment cyclopeptide analogue and polyethylene glycol derivative thereof |
| CN1927879B (en) * | 2006-09-25 | 2010-11-24 | 吉林大学 | Thymopentin active isomer and its application in medicine preparation |
| WO2008151512A1 (en) * | 2007-06-12 | 2008-12-18 | Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. | Site-specific pegylated linear salmon calcitonin derivatives |
| US9464128B2 (en) | 2007-06-12 | 2016-10-11 | Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. | Site-specific pegylated linear salmon calcitonin analogues |
| CN102796168A (en) * | 2011-05-27 | 2012-11-28 | 首都医科大学 | Compounds with thrombolytic activity and preparation method and application thereof |
| CN107428800A (en) * | 2015-07-08 | 2017-12-01 | 中国食品发酵工业研究院 | A kind of active peptide for suppressing ampa receptor and its preparation method and application |
| WO2017004811A1 (en) * | 2015-07-08 | 2017-01-12 | 中国食品发酵工业研究院 | Active peptide for inhibiting ampa receptor and preparation method and use thereof |
| JP2018521650A (en) * | 2015-07-08 | 2018-08-09 | チャイナ ナショナル リサーチ インスティテュート オブ フード アンド ファーメンテーション インダストリーズ | Active peptides that inhibit AMPA receptors and methods for their preparation and uses thereof |
| US10800810B2 (en) * | 2015-07-08 | 2020-10-13 | China National Research Institute Of Food And Fermentation Industries | Active peptide for inhibiting AMPA receptor and preparation method and use thereof |
| CN107428800B (en) * | 2015-07-08 | 2020-11-27 | 中国食品发酵工业研究院 | Active peptide for inhibiting AMPA receptor and preparation method and application thereof |
| JP2022541240A (en) * | 2019-07-17 | 2022-09-22 | パーシピアド，インコーポレイテッド | Boron-containing RHO kinase inhibitor |
| JP7336017B2 (en) | 2019-07-17 | 2023-08-30 | パーシピアド，インコーポレイテッド | Boron-containing RHO kinase inhibitor |
| CN112315909A (en) * | 2020-11-05 | 2021-02-05 | 南开大学 | A kind of functionalized polymer micelle PM-TLK and its preparation method and application |
| CN112315909B (en) * | 2020-11-05 | 2023-02-17 | 南开大学 | A kind of functionalized polymer micelle PM-TLK and its preparation method and application |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102174084A (en) | 2011-09-07 |
| CN102174084B (en) | 2015-11-18 |
| CN1781933B (en) | 2011-07-20 |
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