CN106539814A - Interferon gene stimulatory protein(SP)（STING）Application of the agonist in the diseases such as resisting rheumatoid arthritis - Google Patents
Interferon gene stimulatory protein(SP)（STING）Application of the agonist in the diseases such as resisting rheumatoid arthritis Download PDFInfo
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to pharmaceutical technology field, specially includes the application of ring dinucleotide cGAMP, c-di-AMP, c-di-GMP and its sulphur-substitutive derivative in the autoimmune diseasees such as treatment rheumatoid arthritis using STING agonist.Present invention research shows that STING agonist can suppress arthroncuss, reduces arthritis index, lowers IL-17, and TNF-α, IL-1 β, IL-6 are expressed, therefore, STING agonist can be used for the medicine for preparing the autoimmune diseasees such as treatment rheumatoid arthritis.
Description
Technical field
The invention belongs to biomedicine technical field, and in particular to STING agonist includes the application in resisting rheumatoid arthritis and in the autoimmune disease medicine such as resisting rheumatoid arthritis is prepared such as ring dinucleotide cGAMP, c-di-AMP.
Background technology
Rheumatoid arthritiss, English entitled Rheumatoid Arthritis, referred to as RA are a kind of autoimmune diseasees of chronic inflammatory systems.With joint and periarticular tissue nonsuppurative inflammation etc. as principal character, the basic pathological changes of rheumatoid arthritiss are synovitis, acute stage synovial membrane swelling, ooze out, neutrophil infiltration rheumatoid arthritiss；Chronic phase synovial hyperplasia is plump, forms pannuss；The latter be cause destruction of joint, joint deformity, dysfunction, make disease enter the irreversible stage pathologic basis.In addition to features above, patient with rheumatoid arthritis can be found various autoantibodys, therefore claim rheumatoid arthritiss simultaneously with extra-articular manifestations such as heating, anemia, scleritis, subcutaneous nodule, pericarditiss, vasculitises and lymph enlargements in serum.Rheumatoid arthritiss have morbidity all over the world, but every country is different with the prevalence in area, whole world prevalence average 1% or so（0.3%～2.1%）.Rheumatoid arthritiss are multiple in women, and the quantity of female patient is 3 times of male.Sickness rate increases with age growth, often in 40～morbidity over fifty years old.China's patient with rheumatoid arthritis is light on disease progression and lesion degree compared with western countries, and prevalence about 0.32%～0.36%, is many with northeast, North China.
Rheumatoid arthritiss, are a kind of complicated immune diseases, and at present to think that primary disease belongs to a kind of autoimmune disease, its initiation factor is unclear, it may be possible to infectants more（Such as virus, mycoplasma or antibacterial etc.）Into after human body, its contained some composition（Such as oligosaccharide or glycopeptide fragment）Absorbed and be combined in the proteoglycan synthesized by synovial cell by intraarticular synovial cell so as to which structure changes and has antigenicity.It is additionally relevant with inherited genetic factorss, it has been found that the tumor susceptibility gene of rheumatoid arthritiss.After infectants enter human body, its contained some composition is absorbed and is combined in the proteoglycan synthesized by synovial cell by intraarticular synovial cell so as to which structure changes and has antigenicity.This autoantigen can not only make body produce antibody（IgG）, change while also result in the Fc fragment structures of IgG molecules, form new antigenic determinant, so as to excite another kind of antibody to be formed, i.e. rheumatoid factor（RF）.The immune complex that the RF and IgG of various immunoglobulin classes is formed is present in blood circulation.RF and immunoglobulin can synthesize in intraarticular and be combined into immune complex, and in circulation, RF-IgG complex can also be deposited on local organization, and this has substantial connection with organ outside joint and joint and lesion tissue.In synovium of joint, RF-IgG complex can be fixed and activating complement, produce C3a and C5a, attract neutrophilic granulocyte and mononuclear cell to ooze out.Neutrophilic granulocyte, mononuclear cell and synovial cell（A type cells）After having swallowed above-mentioned immune complex, lysosomal enzyme is activated and synthesizes and discharge, including neutral protease, collagenase etc. and various media, such as prostaglandin, leukotriene, IL-1 β, TNF-α, IL-17 etc., cause the destruction of synovial membrane and articular cartilage.
Rheumatoid arthritiss relevant cell factor IL-1 β, IL-2, IFN-γ, TNF-α, IL-6 etc. cause the generation of immune impairment, are the key factors for causing rheumatoid arthritiss chronic inflammatory disease（RN Maini, PC Taylor, Annual review of medicine,
2000, Annual Review of Medicine,Vol. 51: 207-229）.Metalloproteases, nuclear Factor-Kappa B (nuclear factor of kappa B, NF- κ B) and osteopontin etc. are also closely related with the pathogenic and joint damage of rheumatoid arthritiss etc. in addition.
Rheumatoid arthritiss relevant cell factor IL-1 β and TNF-α are the important inflammatory mediators in the rheumatoid arthritiss generally acknowledged at present.Main Function mechanism of the IL-1 β in the Development process of rheumatoid arthritiss is:Make synovial cell and chondrocyte synthesis and discharge collagenase and other protein resolvases, and suppress chondrocyte synthetic proteinses polysaccharide matrix, so as to play an important role in the Development process of rheumatoid arthritiss.In recent years, find that what is existed in a large number learns active IL-17 with raw in rheumatoid arthritis people's synovial membrane supernatant, inflammatory cell TNF secretion-α and IL-1 β can be remarkably promoted, TNF-α and IL-1 β have synergism with other inflammatory cytokine, promote indirectly the development of rheumatoid arthritiss.TNF-α overexpression can cause mice that severe arthritic occurs, and suppress TNF-α which can be prevented to occur, and can improve rheumatoid arthritiss clinical symptoms with the medicine of blocking TNF-α activity.In patient with rheumatoid arthritis affected joints, TNF-α can promote the generation of IL-6 in synovial cell, and co-induction VEGF.The research of the calendar year 2001s such as Yoccum shows：In rheumatoid arthritis disease active stage or progressive stage, TNF-α high-level secretory causes the destruction of clinical symptoms and local joint tissue, and chronic phase TNF-α level of relative is low and stable.In serum, TNF-α raises the activeness or seriousness that may point out disease.TNF-α is referred to as " the sister cell factor " with IL-1 β, play a part of jointly " center criminal ", their effect and its scope of target cell have very big similarity, TNF-α is often simultaneously synthesizing and secretion with IL-1 β, the generation of itself is increased with autocrine mode stimulating expression of macrophage, and the synthesis of other side can be promoted, such as, TNF-α can stimulate synovial cell and chondrocyte synthesis PGE2 and collagenase, cause the destruction of bone and cartridge adsorption, promotion fibroblast proliferation (Arend. WP, 2001, Semin
Arthritis Rheurn, 30:1~6)。
IL-17 can remarkably promote inflammatory cell secretion IL-1 and TNF-α.IL-17 is shared with IL-1 β, TNF-α can strengthen 21 family member of activator protein, early growth response gene, the expression of NF-kappaB in osteoblast, and can raise the expression of IL-6, IL-8（Granet C et al, 2004）.IL-17 and the effective synergism of other inflammatory cytokine, so as to promote the development of rheumatoid arthritiss.There is the substantial amounts of IL-17 with biological activity in rheumatoid arthritis people's synovial membrane supernatant, and high-caliber IL-17 is found in its synovial membrane.Hwang etc. analyzes patient's RA synovial membrane mononuclear cell and peripheral blood lymphocytes with the polymerase chain reaction of reverse transcription in 2005, check the expression of IL-17 in base, and the stimulated lower IL-17 expression of receptor situation of fibroblast sample synovial cell, as a result synovial membrane monocytes IL-17 are found, and fibroblast sample synovial cell IL-17 expression of receptor strengthens.In the synovial tissue of patient with rheumatoid arthritis, IL-17 receptor blood vessels account for percentage ratio highest；IL-17 has great expression in patient with rheumatoid arthritis synovium of joint and synovial fluid, therefore effects of the IL-17 in rheumatoid arthritiss is increasingly subject to pay attention to.Research finds that IL-17 is to play its effect in RA morbidities by inducing the generation of other cytokines, protease, adhesion molecule.It is now recognized that osteoclasia mechanism is potentially included during IL-17 promotes rheumatoid arthritiss：Induction IL-1 β and TNF-α are produced, and strengthen indirectly destruction of joint；Increase the quantity of receptor activator of NF-κB ligand and core stimulating factor receptor, destruction both with the balance of OPG and increase osteoclasia；Also directly acting on destruction osteocyte stimulates the differentiation and activation of osteoclast.Bush etc. can significantly mitigate the swelling of rat pawl in the fusion protein treatment complete Freund's adjuvant arthritis model Mus with IL-17 receptors in 2002；Luberts is eased with IL-17 (+) serum of rabbit-anti Mus, histological examination arthritic symptom and cartilage, the erosion of bone in the research report of 2004, and the expression of cytokine such as IL-1 β, IL-6 related to inflammation is also remarkably decreased.
In Patients with Rheumatoid Arthritis and synovial fluid, IL-6 levels are raised, and IL-6 induces high gamma Globulin and autoantibody to produce, including rheumatoid factor as B cell differential factor（K Ishihara, T Hirano, Cytokine ＆ growth
Factor reviews, 2002, Volume 13, Issues 4-5, Pages 357-368）.IL-6 can induce osteoclast precursor to be divided into real osteoclast, therefore, IL-6 may be relevant with bone and cartilage destruction and osteoporosis that patient with rheumatoid arthritis is related.IL-6R can mediate IL-6 to play pleiotropy Role in Plant Signal Transduction, IL-6/IL-6R complex gp130 (glycoprotein 130), by IL-6 signals incoming cells play biological effect.Now with humanization anti-IL-6R antibody be blocking IL-6 is combined with IL-6R, impact IL-6 effect, intervention IL6 activity be also a kind of rheumatoid arthritis treatment approach.
There is panimmunity cell to participate in and mediated autoimmune inflammation in rheumatoid arthritiss, mainly including T, bone-marrow-derived lymphocyte, macrophage, neutrophilic granulocyte etc..Wherein it is worth noting that in CD4+T cells various subgroups RA cause a disease in play the part of important role.CD4+CD25+ (Treg) cell has immunologic tolerance, suppresses the multiplication capacity of autologous CD4+T cells（Ehrenstein MR., Evans JG,
Singh A, et al., 2004）.The proportional imbalance of Th1 cell Th2 cells is also closely related with the pathogenic and joint damage of rheumatoid arthritiss etc..Medicine for treating rheumatoid arthritis treatment mainly includes nonsteroidal anti-inflammatory agent, acts on antirheumatic, immunosuppressant, immunity and biological preparation and plant amedica etc. slowly.（1）Nonsteroidal anti-inflammatory agent（2）Antirheumatic（3）Yun Ke is technetium methylenediphophonate（4）Glucocorticoid hormone（5）Biological preparation（6）Plant amedica, such as Radix Tripterygii Wilfordii, white peony root's total glycoside, sinomenine etc..
At present in the treatment of rheumatoid arthritis, there are various biological preparation to go through to list, important function has been played in the treatment of refractory rheumatoid arthritis.1. infliximab：Also referred to as TNF-α chimeric monoclonal antibodies, clinical trial are proved obtain satisfactory effect with Infliximab to the rheumatoid arthritis patients that methotrexate etc. is failed to respond to any medical treatment（Marc Feldmann and Ravinder
N. Maini,Annual Review of Immunology,2001,Vol. 19: 163-196）.2. Embrel：The fusion protein of people's restructuring TNF receptor p75 and IgGFc sections.3. adalimumab：For the complete humanized monoclonal antibody of TNF-α.4. trastuzumab：IL-6 receptor antagonists, are mainly used in middle severe rheumatoid arthritis, and the patient for reacting not good enough to TNF-α antagonist may be effectively.5. IDEC-C2B8 Rituximab.
Interferon gene stimulatory protein(SP)（STING）It is a kind of transmembrane protein, generally in 152-173 positions region（Dimerization domain, DD）Handing-over forms dimer and in self suppression state.When by some ligands（Such as CDN）Stimulation after molecular configuration change and be activated, recruit Cytoplasm in TANK combine kinases 1（TANK-binding kinase 1, TBK1）, phosphorylations of the TBK1 to IRF3 is mediated, element is caused interference with（Interferon, IFN）- β and other various kinds of cell elements（cytokines）Formation.The generation of IFN β is mark (the Yasuo Tanaka ＆ of STING activation
Zhijian J. Chen. Sci Signal. 2012 Mar 6; 5(214)).Ring dinucleotide cGAMP, is that the unique class for up to the present finding can directly activate the STING agonist that Mus source can activate people source STING albumen again.
Agonist is referred to and can be combined with the protein molecular of receptor on cells or signal transduction pathway, and produces the chemicals or medicine of the characteristic physiological efficiency of natural materials.Ring dinucleotide cGAMP, as the native agonist of STING, can induce I interferon to produce（X Cai, YH Chiu, ZJ Chen
,Molecular cell, Volume 54, Issue 2, 24 April 2014, Pages 289–296）.STING activator is ring dinucleotide, including：c-di-AMP, c-di-GMP,
C-di-IMP, c-AMP-GMP, c-AMP-IMP, c-GMP-IMP etc..
The content of the invention
It is an object of the invention to provide application of the STING agonist in treatment rheumatoid arthritiss.
The present invention also aims to propose application of the STING agonist in treatment medicine for treating rheumatoid arthritis is prepared.
Experimentation of the present invention shows that STING agonist can mitigate arthroncuss, lowers IL-17, and TNF-α, IL-1 β, IL-6 expression act on obvious resisting rheumatoid arthritis, can be used to prepare resisting rheumatoid arthritis medicine.
Dinucleotide cGAMP is mentioned above, specified otherwise is such as not added with, is referred both to C20H22N10O13P2.2NH4,
No. CAS is 1441190-66-4.
STING is mentioned above, is specified protein title, be such as not added with explanation, it is consistent with most open source literatures and ncbi database, European gene database.Its GENE is entitled：TMEM173；GENE ID are：340061；Other names disclosed in STING include：Transmembrane Protein 173,
ERIS, MITA, MPYS, NET23, SAVI, STING, hMITA, hSTING。
The STING agonist being mentioned above, including but not limited to c-di-AMP, c-di-GMP, c-di-IMP,
C-AMP-GMP, c-AMP-IMP, c-GMP-IMP and sulfur substituent and mixture.
Specific embodiment
Present disclosure is illustrated below by embodiment.In the present invention, it, in order to preferably illustrate the present invention, is not for limiting the scope of the present invention that embodiments discussed below is.
Embodiment
1
：
STING
The preparation of agonist
The preparation of cGAMP：cGAMP （Cyclisation-GMP-AMP）Under by activation condition of the literature method after with reference to DNA, by cyclisation cGMP-AMP dinucleotide synzyme（cGAS）Catalyze and synthesize.Purity is more than 98%.（Pingwei Li, et al., Immunity, 2013,
39(6), 1019-1031.）.Thio cGAMP, c-di-AMP, thio c-di-AMP, c-di-GMP are purchased from Sigma companies or Invivogen companies.
Embodiment
2
：Rheumatoid arthritis in rats model and
STING
Anti-depressant medications are treated
SD rats（Purchased from Beijing Vital River Experimental Animals Technology Co., Ltd.）, female, 70.Test medicine title：STING agonist（Prepare with reference to embodiment 1）.Character：White powder.Solvent：Normal saline.Compound method：It is configured to the solution of desired concn before use with normal saline solution.Dosage is：20 mg/kg .Administration number of times：Once a day, continuous 14 days.80 mouse are randomly divided into into 8 groups, 10 per group.The stable common 0.25m L of the emulsifying agent of II Collagen Type VI and complete Freund's adjuvant are injected using root of the tail portion, back, 3 points of foot plantar injection（II Collagen Type VI is purchased from sigma companies with complete Freund's adjuvant）, after inducing 7 days, 0.1mL of the subcutaneous booster injection in foot plantar is placed in mixture of ice and water daily, carries out cold-damp and irritate 1 hour, continuous 2 weeks.The active state change of observation rat, redness and swelling of joints situation, measurement rat paw portion thickness.Start within 14th day it is observed that mice arthroncuss, the 15th day beginning drug administration by injection, matched group are replaced with normal saline.Dexamethasone（Purchased from Sigma companies）It is administered as positive controls daily.Sufficient plantar thickness and arthritis factor are determined daily, and analysis result, data are represented with x ± s, processed using SPSS10.0 softwares, using one factor analysis of variance（one-way ANOVA）The significance of each group knurl weight difference, significance level a=0.05 are compared in inspection.Mouse arthritis methods of marking：After rat modeling success, at the same observe arthroncuss situation, 4 days scoring 1 time (0 point:Without redness;1 point:Little toe joint swelling;2 points:Toe joint and pedal swelling;3 points:Sufficient pawl below ankle joint swells;4 points:Including the whole sufficient pawl swellings including ankle joint), it is up to 16 points.The inflammatory score sum in 4 joints of every rat represented with AI (arthritis index) or arthritis factor, takes the arthritis factor that median represents this group.Test result indicate that：STING activator can significantly inhibit mice arthroncuss（As shown in table 1）.
Table
1 STING
Therapeutical effect of the agonist to subcutaneous rat arthroncuss
（N=10, mean ± SD）
Group
Sufficient plantar thickness（cm）
AI (arthritis factor)
Model control group
7.634±0.215
9
CGAMP groups
5.194±0.253
** 4
Thio cGAMP groups
4.642±0.189
** 3
C-di-AMP groups
5.473±0.276
** 4
Thio c-di-AMP groups
4.765±0.324
** 3
C-di-GMP groups
6.639±0.273
* 6
Positive controls（Dexamethasone）
4.763±0.253
4
Note：*P<0.05 vs model control group；**P<0.01 vs model control group.
Embodiment
3
：Rheumatoid arthritis relevant cell factor is determined
Muroid rheumatic arthritis model, Drug therapy are set up with reference to embodiment 2.Anesthetized rat, puts to death respectively, and inguinal artery takes blood, and 3000r/min centrifugation 15min take supernatant, detect the expression of IL-1 β, IL-17 and TNF-α cytokine with ELISA kit（ELISA kit is purchased from R＆D companies）.ELISA results show：STING agonist can significantly reduce the expression of rheumatoid arthritis relevant cell factor, the effect with rheumatoid arthritis（As shown in table 2-5）.
Table
2 STING
Agonist is to rheumatoid arthritis relevant cell factor
IL-1
The regulating and controlling effect of β
（N=10, mean ± SD）
Group
IL-1 βProtein concentration（pg/ml）
Model control group
55.83±3.74
CGAMP groups
34.65±2.57
**
Thio cGAMP groups
36.77±3.99
**
C-di-AMP groups
42.45±2.55
**
Thio c-di-AMP groups
33.12±4.61
**
C-di-GMP groups
42.32±4.66
*
Note：*P<0.05 vs model control group；**P<0.01 vs model control group.
Table
3 STING
Activator is to rheumatoid arthritis relevant cell factor
IL-17
Regulating and controlling effect
（N=10, mean ± SD）
Group
IL-17 protein concentrations（pg/ml）
Model control group
36.88±2.21
CGAMP groups
28.67±1.76
**
Thio cGAMP groups
27.76±2.13
**
C-di-AMP groups
29.34±1.56
**
Thio c-di-AMP groups
26.22±1.68
**
C-di-GMP groups
30.37±2.13
*
Note：*P<0.05 vs model control group；**P<0.01 vs model control group.
Table
4 STING
Activator is to rheumatoid arthritis relevant cell factor
TNF-
The regulating and controlling effect of α
（N=10, mean ± SD）
Group
TNF-α protein concentration（pg/ml）
Model control group
53.12±2.01
CGAMP groups
44.67±2.12
**
Thio cGAMP groups
43.26±2.22
**
C-di-AMP groups
45.12±1.61
**
Thio c-di-AMP groups
43.89±2.19
**
C-di-GMP groups
47.67±3.30
*
Note：*P<0.05 vs model control group；**P<0.01 vs model control group.
Table
5 STING
Activator is to rheumatoid arthritis relevant cell factor
IL-6
Regulating and controlling effect
（N=10, mean ± SD）
Group
IL-6 protein concentrations（pg/ml）
Model control group
89.91±2.46
CGAMP groups
57.12±1.66
**
Thio cGAMP groups
47.11±3.54
**
C-di-AMP groups
46.22±2.69
**
Thio c-di-AMP groups
53.86±2.47
**
C-di-GMP groups
70.42±2.75
**
Note：*P<0.05 vs model control group；**P<0.01 vs model control group.
Embodiment
4
Rheumatoid arthritiss mouse model and
STING
Anti-depressant medications are treated
Kunming mouse, 6～8 week old, body weight about 20g, male, purchased from Beijing company of dimension tonneau China.By CII（Purchased from Sigma companies）It is dissolved in 0.1 mol/L acetic acid, the stirring at 4 DEG C is allowed to fully dissolving, and mass concentration is 2g/L, and 4 DEG C overnight;Again by CII and Freund's complete adjuvant（Purchased from Sigma companies）Equal-volume mixing, emulsifying, make CII Emulsions, and concentration is 1g/L.Mice 80 is chosen, right metapedes plantar intradermal injection (0.1 mL/ only) of the Emulsion after preparation in mice is caused into inflammation.Modeling successful mice is randomly divided into into 8 groups, 10 per group, respectively dexamethasone is used as positive controls (1 mg/kg), model control group (injecting normal saline) and 5 STING activator administration groups（20 mg/kg）, first immunisation start after 21 days administration.STING activator medicine prepares reference implementation example 2.The daily lumbar injection of experimental group is accordingly treated for 1 time by reagent, and matched group gives the normal saline of same volume, observes the swelling of 4 toes of mice, congested and deformation.The AI (arthritis index) of mice or arthritis factor evaluation methodology are with reference to embodiment 2.Test result indicate that：STING activator can significantly inhibit mice toes arthroncuss, reduce the arthritis factor of mice（As shown in table 6）.
Table
6 STING
Therapeutical effect of the agonist to the subcutaneous toes arthroncuss of mice
Group
AI (arthritis factor)
Model control group
12
CGAMP groups
6
Thio cGAMP groups
5
C-di-AMP groups
5
Thio c-di-AMP groups
4
C-di-GMP groups
6
Positive controls（Dexamethasone）
5。
Claims (7)
1. application of the STING agonist in resisting rheumatoid arthritis is used.
Application of the 2.STING agonist in resisting rheumatoid arthritis medicine is prepared.
3. the application using STING agonist in treatment autoimmune disease.
4. application of the STING agonist in anti-autoimmune disease medicine is prepared is used.
5. application of the STING agonist in the autoimmune diseasees such as resisting rheumatoid arthritis according to claim 1-4, it is characterised in that：Suppress arthroncuss, reduce arthritis index, lower RA relevant cell factor IL-17, TNF-α, IL-1 β, IL-6 expression.
6. the STING agonist described in claim 1-4, including but be not restricted to c-di-AMP, c-di-GMP, c-di-IMP, c-AMP-GMP, c-AMP-IMP, c-GMP-IMP, sulfur substituent and compositionss.
7. routinely pharmaceuticss make various dosage forms to the STING agonist according to claim 1-4, described dosage form includes one or more in tablet, capsule, granule, suspensoid, Emulsion, solution, syrup or injection etc., takes oral or injection（Including one or more in intravenous injection, intravenous drip, intramuscular injection or subcutaneous injection etc.）One or more route of administration in carries out the prevention or treatment of the autoimmune diseasees such as resisting rheumatoid arthritis.
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