Anti-inflammatory Activity of a Systemic STING Inhibitory Non-Nucleotide

系统性 STING 抑制性非核苷酸的抗炎活性

基本信息

批准号：
10382621
负责人：
GLEN N BARBER
金额：
$ 30万
依托单位：
STINGINN, LLC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-17 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10382621
关键词：
Anti-Inflammatory Agents Antibodies Bacteria Barbering Binding Biological Assay Cell Nucleus Cell division Cells Chemicals Chronic Clinical Trials Collaborations Cyclic GMP Cytosol Cytotoxic T-Lymphocytes DNA DNA Damage Data Dinucleoside Phosphates Disease Disease model Evaluation Event Exhibits Family Formulation Generations Genetic Transcription Graft Rejection Host Defense Human Immune Immune system Immunization Immunologic Receptors Infection Inflammation Inflammatory Interferon Type I Interleukin-10 Laboratories Lead Listeria monocytogenes Malignant Neoplasms Mus Mutation Nucleic Acids Pathway interactions Patients Periodicity Pharmaceutical Preparations Pharmacodynamics Production Proteins Regulation Reporting STING agonists Safety Signal Transduction Stimulator of Interferon Genes Systemic Lupus Erythematosus T cell response Therapeutic Agents Three Prime Repair Exonuclease 1 Tissue Transplantation Toll-like receptors Universities Vascular Diseases adaptive immunity antagonist autoinflammatory base clinical development cytokine design drug efficacy ds-DNA efficacy evaluation gut inflammation high throughput screening in vivo infancy inhibitor innate immune pathways insight medical schools microbial mouse model novel pathogen phase I trial prevent pseudotoxoplasmosis syndrome response screening sensor small molecule

项目摘要

PROJECT SUMMARY Cellular innate immune sensors, such as STING (STIMULATOR OF INTERFERON GENES), have evolved to detect microbial infection of the cell. STING controls the potent cytosolic DNA-stimulated innate immune pathways and is activated by cyclic dinucleotides (CDNs) such as cyclic di-GMP and cyclic-di-AMP secreted by intracellular bacteria following infection. Alternatively, STING can be activated by cyclic GMP-AMP (cGAMP) generated by a cellular cGAMP synthase cGAS (MB21D1) after association with aberrant cytosolic dsDNA species, which can include microbial DNA or self-DNA leaked from the nucleus. Association with CDNs enables STING to activate the production of type I interferon (IFN) and pro-inflammatory cytokines, which facilitate adaptive immunity. The activation of STING is critical for protection against microbial infection and cancer. However, chronic STING activation is a leading cause of autoinflammatory disease such as severe systemic lupus erythematosus (SLE), STING associated vasculopathy with onset in infancy (SAVI) inflammation of the gut, tissue transplant rejection and others. Here, we describe a new generation of novel small STING antagonists that inhibit STING signaling, for evaluation as anti-inflammatory therapeutic agents. The compounds have been generated by STINGINN LLC, based in Miami, in collaboration with the University of Miami School of Medicine, FL.

项目摘要细胞先天免疫传感器，例如刺激（干扰素基因的刺激剂），已经演变为检测细胞的微生物感染。 sting控制有效的胞质DNA刺激的先天免疫途径并被环状二核苷酸（CDN）激活感染后细胞内细菌。另外，可以通过环状GMP-AMP（CGAMP）激活刺激与异常胞质dsDNA相关后，由细胞CGAMP合酶CGA（MB21D1）产生物种，其中可能包括从细胞核泄漏的微生物DNA或自动-DNA。与CDN的关联启用激活I型干扰素（IFN）和促炎细胞因子的产生，这有助于自适应免疫。刺激的激活对于防止微生物感染和癌症至关重要。但是，慢性刺激激活是自发疾病的主要原因，例如严重的全身性狼疮红斑（SLE），sting sting与婴儿期（SAVI）发作的sting相关的血管病（SAVI）炎症肠道，组织移植排斥等。在这里，我们描述了新一代的新型小刺拮抗剂抑制刺激信号传导，以评估为抗炎治疗剂。化合物已经由Stinginn LLC（总部位于迈阿密）与迈阿密大学医学院合作生产佛罗里达州