Novel regulatory mechanisms and agonists of STING

STING 的新颖调控机制和激动剂

• 批准号: 10655761
• 负责人: Xiaochen Bai
• 金额: $ 68.06万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655761
• 关键词: Activation Analysis; Adaptor Signaling Protein; Agonist; Antigen-Presenting Cells; Antineoplastic Agents; Antiviral Response; Autophagocytosis; Bacteria; Binding; Binding Sites; Biological Assay; Biophysics; C-terminal; Cancer Patient; Cell Aging; Cell membrane; Cells; Chemicals; Clinic; Clinical Trials; Cryoelectron Microscopy; Cyclic GMP; Cytoplasm; Cytosol; DNA; DNA Binding; DNA Damage; DNA Viruses; Data; Defect; Dendritic Cells; Development; Effectiveness; Enzymes; Foundations; Future; Gene Activation; Goals; Golgi Apparatus; Guanosine Triphosphate; Head; Human; IRF3 gene; Immune; Immune checkpoint inhibitor; Immune response; Immunologic Deficiency Syndromes; Immunotherapy; Impairment; Infection; Inflammatory Response; Integral Membrane Protein; Interferon Type I; Interferons; Invaded; Ligand Binding; Ligand Binding Domain; Macrophage; Malignant Neoplasms; Mediating; Membrane; Metabolic; Molecular; Molecular Conformation; Mutation; NF-kappa B; Natural Immunity; Nature; Oral; Pathway interactions; Phagosomes; Pharmaceutical Preparations; Phosphotransferases; Play; Polymers; Production; Research; Resolution; Role; Second Messenger Systems; Side; Signal Pathway; Signal Transduction; Signaling Protein; Stimulator of Interferon Genes; Structure; T-Cell Activation; T-Lymphocyte; TANK-binding kinase 1; Tail; Testing; Therapeutic; Transmembrane Domain; Tumor Immunity; Viral Cancer; Virus; Virus Diseases; Work; anti-PD-1; anti-PD-L1 antibodies; anti-PD1 antibodies; anti-cancer; cancer cell; cancer therapy; cancer type; chemokine; design; endoplasm; fighting; hydrophilicity; improved; interest; loss of function; molecular drug target; neoplastic cell; novel; novel strategies; novel therapeutics; palmitoylation; pathogen; polymerization; recruit; response; scaffold; sensor; synergism; targeted cancer therapy; tool; transcription factor; tumor; tumor progression; viral DNA

Abstract The innate immunity is the first line of defense of our body against invading pathogens such as viruses and bacteria. The cGAS/STING pathway is a recently discovered innate immunity pathway that plays critical roles in eliminating cytosolic DNA virus. Viral DNA in the cytosol is detected by the DNA sensor cyclic-GMP-AMP synthase (cGAS), which becomes active and synthesizes the second messenger cyclic-GMP-AMP (cGAMP) using ATP and GTP as the substrates. cGAMP binds and activates adaptor protein Stimulator of Interferon Genes (STING), a transmembrane protein normally residing on the endoplasmic reticulon (ER) membrane. cGAMP-bound STING polymerizes and translocates to the Golgi apparatus, where it activates the downstream signaling proteins the TBK1 kinase and the transcription factor IRF3. This signaling pathway ultimately leads to a plethora of anti-viral responses, including the production of interferons, induction of inflammatory responses and autophagy. The cGAS/STING can also launch immune responses to self-DNA, such as damaged DNA leaked into the cytosol in cancer cells. In fact, mounting evidence in the past few years have demonstrated the cGAS/STING pathway plays a critical role in immune responses to cancer through several mechanisms. cGAS/STING signaling can boost the effects of immune checkpoint inhibitors such as anti-PD1 and anti-PD-L1 antibodies in cancer therapy, whereas loss of function of the cGAS/STING pathway leads to severe immuno- deficiency and impaired response to immune checkpoint inhibitors. STING therefore has become a major target for cancer therapy in recent years, with several agonists undergoing clinic trials at present. One major goal of this project is to advance our understanding of the fundamental regulatory mechanisms of STING by using cryo-EM structural analyses in combination with biophysical and cell-based functional assays. In addition, our preliminary data revealed a novel cryptic agonist binding site in STING, opening the door to the development of a completely new class of STING agonists. The second major direction of the project is therefore to further characterize this new binding site in STING, and design more potent and specific agonists based on the structures. New STING agonists will be synthesized and tested in biophysical and functional assays, and structurally characterized using cryo-EM. The new agonists could be used as chemical tools for further mechanistic studies, and may be developed into anti-cancer drugs in future.

摘要 先天免疫是我们身体抵御入侵病原体的第一道防线，如病毒和 细菌。CGAS/STING途径是新近发现的一种发挥重要作用的天然免疫途径。 在清除胞质DNA病毒方面。用DNA传感器Cycle-GMP-AMP检测胞浆中的病毒DNA 合酶(CGAS)，它变得活跃，并合成第二信使-环鸟苷-AMP(CGAMP) 以三磷酸腺苷和三磷酸鸟苷为底物。CGAMP结合并激活干扰素接头蛋白刺激物 基因(STING)，一种跨膜蛋白，通常位于内质网(ER)膜上。 CGAMP结合的刺会聚合并转移到高尔基体，在那里它激活下游 信号蛋白：TBK1激酶和转录因子IRF3。这一信号通路最终导致 过多的抗病毒反应，包括产生干扰素，诱导炎症反应 和自噬。CGAS/STING还可以启动对自身DNA的免疫反应，例如DNA损伤 泄漏到癌细胞的胞浆中。事实上，过去几年中越来越多的证据表明， CGAS/STING通路通过多种机制在肿瘤免疫应答中发挥重要作用。 CGAS/STING信号通路可增强抗PD1和抗PD-L1等免疫检查点抑制剂的作用 抗体在癌症治疗中的作用，而cGAS/STING通路功能的丧失导致严重的免疫- 对免疫检查点抑制剂缺乏和反应受损。因此，刺痛已经成为一种主要的 近年来成为癌症治疗的靶点，目前有几种激动剂正在进行临床试验。一大专业 本项目的目标是通过以下方式增进我们对刺痛的基本调控机制的理解 结合生物物理和基于细胞的功能分析，使用低温EM结构分析。在……里面 此外，我们的初步数据显示，在刺痛中有一个新的神秘激动剂结合部位，打开了通往 开发一类全新的刺痛激动剂。该项目的第二个主要方向是 因此，为了进一步表征这种新的结合部位，并设计更有效和更特异的激动剂 基于这些结构。将合成新的STING激动剂，并进行生物物理和功能测试 并用低温电子显微镜对其结构进行了表征。新的激动剂可以作为化学工具用于 进一步的机理研究，并可能在未来开发成抗癌药物。