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

• 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
• 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

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，如STING（干扰素基因刺激物），已经进化为 检测细胞的微生物感染。STING控制有效的细胞溶质DNA刺激的先天免疫 通过环二核苷酸（CDN）激活，如由细胞分泌的环二GMP和环二AMP。 感染后的细胞内细菌。或者，STING可以通过环GMP-AMP（cGAMP）激活。 由细胞cGAMP合酶cGAS（MB 21 D1）在与异常胞质dsDNA结合后产生 物种，其中可以包括微生物DNA或从细胞核泄漏的自身DNA。与CDN的关联使 STING可激活I型干扰素（IFN）和促炎细胞因子的产生， 适应性免疫STING的激活对于防止微生物感染和癌症至关重要。 然而，慢性STING激活是自身炎性疾病如严重全身性炎症的主要原因。 红斑狼疮（SLE），STING相关血管病变与婴儿期发作（SAVI）炎症 肠道组织移植排斥反应等等在这里，我们描述了新一代新型小STING拮抗剂， 其抑制STING信号传导，用于评价作为抗炎治疗剂。这些化合物已经 由总部位于迈阿密的STINGINN LLC与迈阿密大学医学院合作产生， 花期