Targeting IKKepsilon-mediated nucleotide synthesis in KSHV-associated lymphoma

靶向 KSHV 相关淋巴瘤中 IKKepsilon 介导的核苷酸合成

• 批准号: 10762816
• 负责人: Pinghui Feng
• 金额: $ 37.86万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10762816
• 关键词: Acquired Immunodeficiency Syndrome; Antiviral Therapy; Basic Science; Binding; Cell Proliferation; Cells; Cellular Metabolic Process; Citric Acid Cycle; Coupling; Enzymes; Episome; Etiology; Event; G1 Phase; Genome; Glutamine; Herpesviridae; Herpesviridae Infections; Human; Human Herpesvirus 4; Human Herpesvirus 8; IKKepsilon; Immune; Immune response; Individual; Integration Host Factors; Interferons; Investigation; Kaposi Sarcoma; Knowledge; Lymphoma; Lymphoma cell; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Metabolic; Metabolism; Molecular; Morbidity - disease rate; Multicentric Angiofollicular Lymphoid Hyperplasia; Oncogenic Viruses; Outcome; Patients; Phosphorylation; Phosphotransferases; Post-Translational Protein Processing; Proliferating; Protein-Serine-Threonine Kinases; Proteins; Purines; Pyrimidine; Research; Role; Serine; System; Testing; Thymidine Kinase; Tumor Biology; Tumor Cell Biology; Vaccines; Viral; Viral Physiology; Work; anti-viral efficacy; cancer cell; chronic infection; clinical application; deamidation; drug-like compound; effective therapy; efficacy evaluation; gammaherpesvirus; immunodeficient mouse model; insight; interest; mortality; neoplastic cell; novel; nucleotide metabolism; organ transplant recipient; pathogen; primary effusion lymphoma; programs; small molecule; small molecule inhibitor; targeted treatment; tumor; tumor metabolism; virus host interaction

Abstract Title: Targeting IKKepsilon-mediated nucleotide synthesis in KSHV-associated lymphoma Human gamma herpesviruses, including Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), are causative agents of diverse malignancies in immune- compromised individual, including AIDS patients and organ transplant recipients. In addition to KS, KSHV is invariably associated with two types of lymphoma, primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). No vaccine or effective treatment is available for KSHV-associated malignancies, though antiviral therapy targeting viral thymidine kinase is an option with limited efficacy. We have an outstanding interest in virus-host interaction involving innate immune defense system. Recently, we discovered that KSHV exploits the IKKepsilon kinase to reprogram metabolism in KSHV latently-infected PEL cells. Specifically, KSHV activates IKKepsilon to fuel de novo nucleotide synthesis via activating key metabolic enzymes known as glutamine amidotransferases. In doing so, IKKepsilon promotes the proliferation of KSHV-infected PEL cells and depletion of IKKepsilon arrests these cells at G0/G1 phase. This study will delineate the molecular interaction that KSHV activates IKKepsilon in metabolic reprogramming to support immortal proliferation of PEL cells. We have developed novel small-molecule inhibitors of IKKepsilon and glutamine amidotransferases. We will explore these drug-like molecules to target IKKepsilon and glutamine amidotransferase to impede PEL cell proliferation. Our work will not only elucidate fundamental mechanism governing PEL cell metabolism and proliferation, but also provide proof-of-concept that targets host factors to treat KSHV-associated malignancies.

抽象的 标题：针对 KSHV 相关淋巴瘤中 IKKepsilon 介导的核苷酸合成 人类γ疱疹病毒，包括卡波西肉瘤相关疱疹病毒（KSHV）和 EB 病毒 (EBV) 是免疫系统中多种恶性肿瘤的病原体。 受影响的个人，包括艾滋病患者和器官移植接受者。此外 KS、KSHV 总是与两种类型的淋巴瘤相关：原发性渗出性淋巴瘤 （PEL）和多中心卡斯尔曼病（MCD）。没有疫苗或有效的治疗方法 尽管针对病毒胸苷的抗病毒治疗可用于 KSHV 相关恶性肿瘤 激酶是一种功效有限的选择。 我们对涉及先天免疫防御的病毒与宿主的相互作用有着浓厚的兴趣 系统。最近，我们发现 KSHV 利用 IKKepsilon 激酶进行重新编程 KSHV 潜伏感染的 PEL 细胞中的代谢。具体来说，KSHV 激活 IKKepsilon 来提供燃料 通过激活称为谷氨酰胺的关键代谢酶从头合成核苷酸 酰胺转移酶。通过这样做，IKKepsilon 促进了 KSHV 感染的 PEL 的增殖 细胞和 IKKepsilon 的耗竭使这些细胞停滞在 G0/G1 期。这项研究将描绘 KSHV 在代谢重编程中激活 IKKepsilon 的分子相互作用以支持 PEL细胞的永生增殖。我们开发了新型小分子抑制剂 IKKepsilon 和谷氨酰胺酰胺转移酶。我们将探索这些药物样分子 靶向 IKKepsilon 和谷氨酰胺酰胺转移酶以阻止 PEL 细胞增殖。我们的工作 不仅将阐明控制 PEL 细胞代谢和增殖的基本机制， 还提供针对宿主因素治疗 KSHV 相关疾病的概念验证 恶性肿瘤。