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

项目总结 细胞先天免疫感受器，如刺激物(干扰素基因的刺激物)，已经进化到 检测细胞的微生物感染情况。斯汀控制着强大的胞浆DNA刺激的先天免疫 途径，并被由分泌的环二核苷酸(CDN)激活，如cDGMP和cDAMP 感染后的细胞内细菌。或者，刺痛可以被环化的GMP-AMP(CGAMP)激活 细胞内cGAMP合成酶cGAS(MB21D1)与胞浆dsDNA结合后产生 物种，可以包括从细胞核泄漏的微生物DNA或自身DNA。启用与CDN的关联 刺激型干扰素和促炎细胞因子的产生，从而促进 适应性免疫。刺痛的激活对于预防微生物感染和癌症至关重要。 然而，慢性刺痛激活是导致自身炎症性疾病的主要原因，如严重的全身性 红斑狼疮(SLE)，刺痛相关性血管病变起病于婴儿(SAVI)的炎症 肠道、组织移植排斥反应等。在这里，我们描述了新一代新型小刺痛拮抗剂 抑制刺痛信号，用于作为消炎治疗药物的评估。这些化合物已经被 由总部设在迈阿密的STINGINN LLC与迈阿密大学医学院合作生成， 佛罗里达州

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.