CN106540260A - Interferon gene stimulatory protein(SP)（STING）Application of the agonist in anti-alzheimer's disease - Google Patents
Interferon gene stimulatory protein(SP)（STING）Application of the agonist in anti-alzheimer's disease Download PDFInfo
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- CN106540260A CN106540260A CN201510904848.1A CN201510904848A CN106540260A CN 106540260 A CN106540260 A CN 106540260A CN 201510904848 A CN201510904848 A CN 201510904848A CN 106540260 A CN106540260 A CN 106540260A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
Abstract
The invention belongs to pharmaceutical technology field, specially using interferon gene stimulatory protein(SP)（STING）Agonist includes the application of ring dinucleotide cGAMP, c-di-AMP, c-di-GMP and its thio derivative in treatment alzheimer's disease.Present invention research shows that STING agonist can strengthen the cognition of alzheimer's disease model mice and memory ability, suppress neuronal apoptosis, suppress amyloid beta deposition etc..Therefore, STING agonist can be used to prepare medicine resisting Alzheimer disease.
Description
Technical field
The invention belongs to biomedicine technical field, and in particular to STING agonist includes ring dinucleotide cGAMP, c-
The answering in anti-alzheimer's disease and in the neurodegenerative diseases medicine such as anti-alzheimer's disease is prepared such as di-AMP
With.
Background technology
Neurodegenerative diseases are the morbid states of the cellular neural unit forfeiture of a brain and spinal cord.Brain and spinal cord are by god
Jing units composition, neuron have different functions, and such as control motion processes sensory information, and makes decisions.Neurodegenerative diseases
It is, caused by the forfeiture of neuron or its myelin, As time goes on to deteriorate, to cause dysfunction.Nervus retrogression disease
Disease includes：Stages alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, mad cow disease, gram
Refined Er Shi diseases, Huntington's disease, cerebral atrophy, multiple sclerosis, parkinson, primary lateral sclerosiss, spinal cord
Property muscular atrophy, cerebral ischemia, spastic paraplegia, myasthenia graviss.
Alzheimer is a kind of nervous system degenerative disease for carrying out sexual development of onset concealment.Clinically with note
Recall obstacle, aphasia, apraxia, agnosia, the infringement of visual space technical ability, perform function obstacle and personality and behavior change etc. comprehensive silly
Slow-witted performance is characterized, and the cause of disease is unknown so far.Patient was sent out within 65 years old in the past, claimed presenile dementia；Claimed with sequela person within 65 years old senile
It is dull-witted.In all of dementia, with the ratio highest shared by Alzheimer, about 50 ~ 60%.Wherein, women compares male again
It is easier to suffer from, and has 11% in over-65s population, has within more than 80 years old 50% this disease occurs.Its symptom is sent out from disease
After can continue 1 ~ 25 year, and can be increasingly severe, and then cause death.Alzheimer can attack the brain of people, and it is simultaneously
Improper catabiosis.Obtain Alzheimer patient can loss of memory gradually, and occur on language and emotion
Obstacle.When this disease is increasingly severe, sufferer needs other people looking after day and night, therefore sufferer kith and kin in life everyway
Life be often also and then greatly affected.
Alzheimer is still a kind of disease that cannot be effected a radical cure at present, and Alzheimer is found in 1906, German
Neuroscientist likes Ross. the image that alzheimer is obtained with microscope first, record Alzheimer patient's brain
Slight change.He shows the pathological anatomy figure of a female patients, and the intelligence of this women is several years ago gradually mixed toward raw at her
Disorderly.Through pathoanatomical method, he from observed by this female patients brain change be referred to as speckle and entanglement, both
The function that information was linked up and passed to brain neuroblastoma each other will be blocked.
Alzheimer causes cranial nerve cell dead, current A Er in cerebral deposition mainly due to protein
The research of Zi Haimo diseases is concentrated on Amyloid precursor protein (APP), and the albumen is conducive to the formation of destructive speckle in brain.Research
Personnel are verified except Amyloid precursor protein and the speckle for being formed, and affect the development of alzheimer's disease to be likely to other and make
The reason for using mechanism.Before Alzheimer is understood, pathologist just has already known the mankind to the cause of disease of Alzheimer
Cerebral cortex it sometimes appear that the speckle of circle, under the microscope it can be seen that these specklees are the aixs cylinders wrapped up by fine fibre
Constituted with dendron.1853, it was kind of starch depositing that German pathologist Fei Erke (Virchow) claims these deposits, later
Further research learns that they are a kind of protein molecules.1984, Ge Liena (Glenner) and father-in-law (Wong) were first by Ah hereby
Kind of starch deposition is isolated in the meningovascular of Alzheimer disease patient.Soon, Ma Shide (Masters) and Belém rope
Et al. (Beyrenther) also by kind of starch deposition, its molecular weight and aminoacid composition dative are isolated in aging speckle core
It is same that row receive et al. separated kind of starch sedimentary facies.
Starch deposition derives from APP albumen.APP is a kind of transmembrane protein, by larger N ends extracellular region, a cross-film
Area and a less C-terminal intracellular region composition.Jing analyses find that APP molecules can be divided into three from N-terminal to C-terminal, generally
Highly conserved region：E1 regions, E2 regions and C-terminal region.Researcher is proposed and confirms a new A β cell toxicant
Property model：A β by with the interaction of APP (site of effect be APP on A β regions), accelerate APP aggregation, strengthen god
The sensitivity of Jing units, promotes apoptosis.Detailed process is：First, A β as part directly and specifically with positioned at cell
The A β regions of the APP on surface combine, and accelerate APP aggregations；Then caspase or its similar enzyme are in APP695 intracellular regions
It is cut after the Asp664 in domain, the peptide C 31 of 31 amino acid residues of APP C-terminal is discharged（Xinwei Cao,
Thomas C. Südhof. Science. 6 July 2001: Vol. 293 no. 5527 pp. 115-120）.C31 is
Potential cytotoxic molecule, can pass through sequence " GYENPTY " motif thereon (the 681-687th amino acids in APP695
Residue) interact with the multiple proteins such as intracellular Fe65, thus it is speculated that it is multiple ternary to be defined with Fe65 and CP2/LSF/LBP1
Compound, the latter induce the expression of GSK-3 β, so as to cause apoptosis（Dennis J. Selkoe,Science 25
October 2002: Vol. 298 no. 5594 pp. 789-791）.
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 is various with other
Cytokines（cytokines）Formation.The generation of IFN β is mark (the Yasuo Tanaka ＆ Zhijian J. of STING activation
Chen. Sci Signal. 2012 Mar 6; 5(214)).Ring dinucleotide cGAMP, is up to the present find unique
One class 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 natural materials
Characteristic physiological efficiency chemicals or medicine.Ring dinucleotide cGAMP, as the native agonist of STING, can induce I
Property interferon 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 alzheimer's disease.
The present invention also aims to propose application of the STING agonist in treatment alzheimer disease drug is prepared.
Experimentation of the present invention shows that STING agonist can suppress the apoptosis of neurocyte, suppresses amyloid to gather
Collection, improves cognitive competence, acts on significantly anti-alzheimer's disease, can be used to prepare medicine resisting Alzheimer disease.
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, with most open source literatures and NCBI data
Storehouse, European gene database are consistent.Its GENE is entitled：TMEM173；GENE ID are：340061；Disclosed other lives of STING
Name includes：Transmembrane Protein 173, ERIS, MITA, MPYS, NET23, SAVI, STING,
hMITA, hSTING。
APP is mentioned above, is specified protein title, be such as not added with explanation, with most open source literatures and ncbi database,
European gene database is consistent.Its GENE is entitled：APP；GENE ID are：351；Other names disclosed in STING include：AAA,
ABETA, ABPP, AD1I, CTFgamma, CVAP, PN-II, PN2。AD 。
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 its sulphur-substitutive derivative and mixture.
Specific embodiment
Present disclosure is illustrated below by embodiment.In the present invention, embodiments discussed below be in order to
The present invention is preferably illustrated, is not for limiting the scope of the present invention.
Embodiment 1：The preparation of STING agonist
The preparation of cGAMP：cGAMP （Cyclisation-GMP-AMP）Under by activation condition of the literature method after with reference to DNA, by being cyclized
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 equal
Purchased from sigma companies or invivogen companies.
Embodiment 2：Alzheimer disease mouse model and the treatment of STING anti-depressant medications
APP/PS1 transgenic mices are purchased from Ze Sheng Bioisystech Co., Ltd of BeiJing ZhongKe, 5 monthly ages, body weight 24-26g.It is tested
Medicine name：STING agonist.Character：White powder.Solvent：Normal saline.Compound method：It is water-soluble with physiology salt before use
Liquid is configured to the solution of desired concn.Dosage is：7.5mg/kg .Administration number of times：Once a day, continuous 28 days.
Embodiment 3：Morris water mazes verify alzheimer's disease mice cognitive competence
Device:Round pool, diameter 1m, high 50cm, depth of water 30cm, bottom of pond white, water temperature are maintained at 23 ± 2 DEG C；Pool wall subscript
, used as the starting point tested, diversion basin is four quadrants for four equidistant points N, E of note, S, W, in third quadrant central authorities placement platform
(platform is with the pool wall center of circle apart from equal)；1 cm in underwater, makes platform invisible.Peripheral pool posts abundant reference clue
(different colours triangle, square, circle, rhombus are placed in each quadrant) and keep constant, be used for locating platform for mice.
Orientation navigation is tested:Test lasts 6 days altogether, trains 4 times due to fixed time period daily.When training starts, will be flat
Platform is placed in first quartile, and mice is put into pond towards pool wall from any point of four starting points of pool wall.Free video record system
System record mice find platform time and swimming path, 4 times training will mice respectively from four different starting points（It is different
Quadrant）It is put in water.Platform (incubation period is designated as 90 seconds) is can not find after mice finds platform or in 90 seconds, then by experimenter by its
Platform is directed to, is rested 10 seconds on platform, then is tested next time.
Space exploration is tested：After orientation navigation off-test 24h, platform is removed.Then Mus are put into into water by third quadrant
In, swimming path of the Mus in 180s is recorded, record Mus are in target quadrant（Third quadrant）The time of staying and pass through former platform
The number of times of position, observes the space orientation ability of tested Mus.Data are represented with x ± s, at SPSS10.0 softwares
Reason, using one factor analysis of variance（one-way ANOVA）The significance of each group knurl weight difference, significance level a=are compared in inspection
0.05.Experimental result is as shown in Figure 1（A is matched group, and B is cGAMP administration groups, and C is thio cGAMP administration groups, and D is c-di-
AMP administration groups, E are thio c-di-AMP administration groups, and F is c-di-GMP administration groups）, as a result show：STING activator includes
The alzheimer's disease mice of the treatments such as cGAMP has the phenomenon that cognitive competence is lifted
The impact of Fig. 1, cGAMP to alzheimer's disease mice cognitive competence（A is matched group, and B is cGAMP administration groups, and C is sulfur
For cGAMP administration groups, D is c-di-AMP administration groups, and E is thio c-di-AMP administration groups, and F is c-di-GMP administration groups）
Note：*P<0.05 vs A negative control groups；**P<0.01 vs A negative control groups.
Embodiment 4：Alzheimer's disease Mouse brain apoptosis is determined
TUNEL apoptosis test kits（G3250 test kits）Purchased from Promega companies.Mice brain tissues are taken, fixed, paraffin embedding is cut
Piece, dimethylbenzene dewaxing, Gradient elution using ethanol, PBS washings, E.C. 3.4.21.64 incubation at room temperature 10min, after section PBS washings, formaldehyde is solid
It is fixed, wash after adding level pad pre-equilibration, add incubation buffer afterwards（Include level pad, mixture of nucleosides and
RTdT enzymes）, 37 DEG C of lucifuges are incubated 1h, contaminate DAPI altogether, dry in the shade after terminating reaction, and mounting, laser microscope are taken pictures.Experimental result is such as
Shown in Fig. 2（A is matched group, and B is cGAMP administration groups, and C is thio cGAMP administration groups, and D is c-di-AMP administration groups, and E is sulfur
For c-di-AMP administration groups, F is c-di-GMP administration groups）, as a result show：After using cGAMP, mouse brain nerve can be suppressed
The apoptosis of cell.
The impact of Fig. 2, cGAMP to alzheimer's disease mouse intracerebral neuronal apoptosis（A is matched group, and B is cGAMP
Administration group, C are thio cGAMP administration groups, and D is c-di-AMP administration groups, and E is thio c-di-AMP administration groups, and F is c-di-
GMP administration groups）
Embodiment 5：Alzheimer's disease mouse brain staining amyloid proteins
This experiment is thioflavine S Coloration experiments, and experiment flow is：Mice brain tissues are taken, fixed, paraffin embedding, section, dimethylbenzene
Dewaxing, Gradient elution using ethanol, TBS are washed three times, 0.3% thioflavine S（It is dissolved in 50% ethanol）Drip in tissue, be incubated at room temperature 10min,
50% ethanol is washed three times, TBS cleanings, is dried in the shade, and mounting is observed under laser confocal microscope.As shown in Figure 3 (A is experimental result
Matched group, B are cGAMP administration groups, and C is thio cGAMP administration groups, and D is c-di-AMP administration groups, and E given for thio c-di-AMP
Medicine group, F are c-di-GMP administration groups), the STING such as cGAMP activator can significantly reduce the heavy of mouse intracerebral Abeta albumen
Product.
(A is matched group to impact to alzheimer's disease mouse intracerebral Abeta proteinosiss of Fig. 3, cGAMP, and B is
CGAMP administration groups, C are thio cGAMP administration groups, and D is c-di-AMP administration groups, and E is thio c-di-AMP administration groups, and F is c-
Di-GMP administration groups).
Claims (10)
1. application of the STING agonist in anti-alzheimer's disease is used.
Application of the 2.STING agonist in medicine resisting Alzheimer disease is prepared.
Application of the 3.STING agonist in anti-neurodegenerative diseases medicine is prepared.
4. application of the STING agonist in anti-alzheimer's disease according to claim 1, it is characterised in that：Lifting is recognized
Know ability, suppress intracerebral amyloid beta deposition, suppress intracerebral neuronal apoptosis.
5. the STING agonist described in claim 1, including but be not restricted to c-di-AMP, c-di-GMP, c-di-
IMP, c-AMP-GMP, c-AMP-IMP, c-GMP-IMP, and its thio derivative and compositionss.
6. applications of the thio cGAMP in anti-alzheimer's disease is used.
7. applications of the thio cGAMP in medicine resisting Alzheimer disease is prepared.
8. applications of the thio cGAMP in anti-neurodegenerative diseases medicine is prepared.
9. applications of the thio cGAMP in anti-alzheimer's disease according to claim 2, it is characterised in that：Suppress intracerebral
Neuronal apoptosis, suppress intracerebral amyloid beta deposition, lift cognitive competence.
10. routinely pharmaceuticss make various dosage forms, described agent to the STING agonist according to claim 2,3,7,8
Type includes one or more in tablet, capsule, granule, suspensoid, Emulsion, solution, syrup or injection etc., adopts
Take oral or injection（Including one or more in intravenous injection, intravenous drip, intramuscular injection or subcutaneous injection etc.）In
One or more route of administration carries out the prevention or treatment of anti-alzheimer's disease and its directly related neurodegenerative diseases.
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| CN201510904848.1A CN106540260A (en) | 2015-12-09 | 2015-12-09 | Interferon gene stimulatory protein(SP)（STING）Application of the agonist in anti-alzheimer's disease |
| PCT/CN2016/096816 WO2017096963A1 (en) | 2015-12-09 | 2016-08-26 | Use of agonist of stimulator of interferon genes in treating alzheimer's disease |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110755600A (en) * | 2018-07-25 | 2020-02-07 | 聊城市奥润生物医药科技有限公司 | Treatment of alzheimer's disease with natural immune agonists in combination with brain homeostatic regulatory proteins |
| CN110938104A (en) * | 2018-09-21 | 2020-03-31 | 上海迪诺医药科技有限公司 | Cyclic dinucleotide analogs, pharmaceutical compositions and uses thereof |
| CN111135185A (en) * | 2018-11-02 | 2020-05-12 | 杭州星鳌生物科技有限公司 | Natural immune activation through regulating medullary cell triggering receptor TREM2 to inhibit chronic inflammation of cerebral nerve |
| CN114053289A (en) * | 2020-08-06 | 2022-02-18 | 北京箭牧科技有限公司 | Application of ridiflovir in preparation of medicine for preventing and treating nervous system degenerative diseases |
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| KR102530488B1 (en) | 2016-03-18 | 2023-05-08 | 이뮨 센서, 엘엘씨 | Cyclic di-nucleotide compounds and methods of use |
| IL264049B2 (en) | 2016-07-06 | 2023-11-01 | Sperovie Biosciences Inc | Compounds, compositions, and methods for the treatment of disease |
| EP3675859A4 (en) | 2017-08-31 | 2021-06-30 | Sperovie Biosciences, Inc. | Compounds, compositions, and methods for the treatment of disease |
| US11584774B2 (en) | 2017-09-11 | 2023-02-21 | F-star Therapeutics, Inc. | Compounds, compositions, and methods for the treatment of disease |
| WO2019051489A1 (en) | 2017-09-11 | 2019-03-14 | Sperovie Biosciences, Inc. | Compounds, compositions, and methods for the treatment of disease |
| AU2020267486A1 (en) | 2019-05-09 | 2021-11-11 | Aligos Therapeutics, Inc. | Modified cyclic dinucleoside compounds as STING modulators |
| CN112048522A (en) * | 2020-09-02 | 2020-12-08 | 北京百奥赛图基因生物技术有限公司 | Construction method and application of TMEM173 gene humanized and modified animal model |
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Application publication date: 20170329 |