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.

摘要 标题：KSHV相关淋巴瘤中IKKepsilon介导的靶向核苷酸合成 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， 包括艾滋病患者和器官移植接受者。除了 KS、KSHV常与两种类型的淋巴瘤相关，即原发性渗出性淋巴瘤 (PEL)多中心Castleman病（MCD）没有疫苗或有效的治疗方法 可用于KSHV相关的恶性肿瘤，尽管靶向病毒胸苷的抗病毒治疗 激酶是具有有限功效的选择。 我们对涉及先天免疫防御的病毒-宿主相互作用非常感兴趣 系统最近，我们发现KSHV利用IKK激酶重新编程 KSHV潜伏感染的PEL细胞中的代谢。具体来说，KSHV激活IKKKER， 通过激活称为谷氨酰胺的关键代谢酶进行从头核苷酸合成 酰胺转移酶。在此过程中，IKK促进了KSHV感染的PEL的增殖 细胞和IKK β的耗竭将这些细胞阻滞在G 0/G1期。这项研究将描述 KSHV在代谢重编程中激活IKK蛋白以支持 PEL细胞的无限增殖。我们已经开发了新的小分子抑制剂， IKK蛋白和谷氨酰胺转移酶。我们将探索这些药物样分子， 靶向IKK β和谷氨酰胺酰胺转移酶以阻止PEL细胞增殖。我们的工作 将不仅阐明控制PEL细胞代谢和增殖的基本机制， 而且还提供了针对宿主因素治疗KSHV相关的概念验证， 恶性肿瘤。