Novel regulatory mechanisms and agonists of STING

STING 的新颖调控机制和激动剂

基本信息

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
项目类别：
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

项目摘要

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.

抽象的先天免疫是我们身体抵御病毒和病原体等入侵病原体的第一道防线。细菌。 cGAS/STING途径是最近发现的一条发挥关键作用的先天免疫途径消除胞质DNA病毒。 DNA 传感器 cycl-GMP-AMP 检测细胞质中的病毒 DNA 合酶 (cGAS)，变得活跃并合成第二信使环 GMP-AMP (cGAMP) 以ATP和GTP为底物。 cGAMP 结合并激活接头蛋白干扰素刺激剂基因 (STING)，一种跨膜蛋白，通常驻留在内质网 (ER) 膜上。结合 cGAMP 的 STING 聚合并转移到高尔基体，激活下游信号蛋白 TBK1 激酶和转录因子 IRF3。该信号通路最终导致大量的抗病毒反应，包括干扰素的产生、炎症反应的诱导和自噬。 cGAS/STING 还可以对自身 DNA（例如受损 DNA）发起免疫反应渗漏到癌细胞的细胞质中。事实上，过去几年越来越多的证据表明 cGAS/STING 通路通过多种机制在癌症免疫反应中发挥关键作用。 cGAS/STING 信号传导可以增强免疫检查点抑制剂（例如抗 PD1 和抗 PD-L1）的作用抗体在癌症治疗中的应用，而 cGAS/STING 通路功能的丧失会导致严重的免疫- 缺乏和对免疫检查点抑制剂的反应受损。因此，STING 已成为主要的近年来癌症治疗的靶点，目前有几种激动剂正在进行临床试验。一个专业该项目的目标是通过以下方式增进我们对 STING 基本监管机制的理解：使用冷冻电镜结构分析与生物物理和基于细胞的功能测定相结合。在此外，我们的初步数据揭示了 STING 中一个新颖的神秘激动剂结合位点，为开发一类全新的 STING 激动剂。该项目的第二个主要方向是因此，为了进一步表征 STING 中的这个新结合位点，并设计更有效和特异性的激动剂基于结构。新的 STING 激动剂将被合成并在生物物理和功能方面进行测试分析，并使用冷冻电镜进行结构表征。新的激动剂可用作化学工具进一步的机理研究，未来可能开发成抗癌药物。