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（如病毒和 细菌cGAS/STING通路是最近发现的一种先天免疫通路，其在免疫系统中起关键作用。 在清除胞质DNA病毒方面。细胞质中的病毒DNA由DNA传感器cyclic-GMP-AMP检测 合成酶（cGAS），其变得活跃并合成第二信使环GMP-AMP（cGAMP） 使用ATP和GTP作为底物。cGAMP结合并激活衔接蛋白干扰素刺激物 STING基因是一种跨膜蛋白，通常位于内质网（ER）膜上。 cGAMP结合的STING聚合并移位到高尔基体，在那里它激活下游 信号蛋白TBK 1激酶和转录因子IRF 3。这种信号通路最终导致 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，例如受损的DNA 泄漏到癌细胞的胞浆中。事实上，过去几年越来越多的证据表明， cGAS/STING途径通过几种机制在对癌症的免疫应答中起关键作用。 cGAS/STING信号传导可以增强免疫检查点抑制剂如抗PD 1和抗PD-L1的作用 cGAS/STING途径功能的丧失导致严重的免疫缺陷， 缺乏和免疫检查点抑制剂的反应受损。因此，STING已成为一个主要的 近年来，作为肿瘤治疗的靶点，目前有几种激动剂正在进行临床试验。一个主要 本项目的目标是通过以下方式来促进我们对STING的基本调控机制的理解 使用cryo-EM结构分析结合生物物理和基于细胞的功能测定。在 此外，我们的初步数据揭示了STING中的一个新的隐蔽激动剂结合位点，为STING打开了大门。 开发了一种全新的STING激动剂。该项目的第二个主要方向是 因此，进一步表征STING中的这个新结合位点，并设计更有效、更特异的激动剂 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。 测定，并使用cryo-EM进行结构表征。新的激动剂可用作化学工具， 进一步的机制研究，并可能在未来开发成抗癌药物。