Evaluation of therapeutic benefits of HBV nucleocapsid assembly inhibitors

乙型肝炎病毒核衣壳组装抑制剂的治疗效果评估

• 批准号: 9031576
• 负责人: Yanming Du
• 金额: $ 18.3万
• 依托单位: BARUCH S. BLUMBERG INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9031576
• 关键词: Evaluation; therapeutic; benefits; HBV; nucleocapsid

Contact PD/PI: Guo, Ju-Tao TITLE Evaluation of therapeutic benefits of HBV nucleocapsid assembly inhibitors ABSTRACT This is a proposal to determine the feasibility and therapeutic benefits of newly discovered benzamide derivatives (BAs) as mono-therapeutic agents or in combination with nucleoside analogues for the treatment of chronic hepatitis B. BAs were identified in our laboratory as inhibitors of hepatitis B virus (HBV) pregenomic (pg) RNA encapsidation, which is essential for the subsequent viral DNA synthesis. They are mechanistically distinct from, and should thus complement, the currently FDA-approved antiviral medications. In addition, inhibition of pgRNA encapsidation, or the nucleocapsid assembly, should not only preclude HBV genome replication and virion production, it might also disrupt the metabolism of HBV pgRNA-reverse transcriptase (RT) complex and core protein, which could consequentially interfere with the host innate antiviral immune response and cccDNA function in the infected hepatocytes. Unlike other pgRNA encapsidation inhibitors reported thus far, our benzamide pgRNA encapsidation inhibitors also effectively inhibit woodchuck hepatitis virus (WHV), which allows for the evaluation of the therapeutic benefits of this class of antivirals in a hepadnavirus chronically infected animal model for the first time. We, therefore, propose in this project to perform further lead optimization, and advance compounds with the most favorable ADME, safety and pharmacokinetic (PK) profiles for antiviral efficacy study in the WHV-infected woodchucks in vivo. Meanwhile, we will continue our efforts toward understanding the molecular mechanism by which BAs inhibit HBV nucleocapsid assembly and their consequential impacts on the interaction between HBV and its host hepatocytes. At the completion of this project, we will have a better understanding of the potential clinical benefits of pgRNA encapsidation-targeted antiviral therapy, either alone or in combination with nucleoside analogues in particular, and strategic insights in to the development of antiviral regimes for the cure of chronic hepatitis B infection in general. A decision on further preclinical/clinical development of the lead BAs compounds will be made accordingly. Project Summary/Abstract Page 7

联系PD/PI：郭菊涛 标题 乙肝病毒核衣壳组装抑制剂的疗效评价 摘要 这是一项确定新发现的苯甲酰胺的可行性和治疗益处的建议。 衍生物(BA)作为单一治疗药物或与核苷类似物联合治疗 在我们实验室中，慢性乙肝bas被确认为乙肝病毒前基因组的抑制物。 (PG)RNA封装，这对随后的病毒DNA合成是必不可少的。它们是机械的 有别于目前FDA批准的抗病毒药物，因此应该是它们的补充。此外, 抑制pgRNA包裹体或核衣壳组装，不应仅仅排除乙肝病毒基因组 复制和病毒粒子的产生，它还可能扰乱HBVpgRNA逆转录酶的代谢 (RT)复合体和核心蛋白，可能因此干扰宿主的先天抗病毒免疫 感染肝细胞的应答和cccDNA功能。与其他pgRNA包埋抑制剂不同 到目前为止，我们的苯甲酰胺pgRNA包埋抑制剂也能有效地抑制土拨鼠肝炎。 病毒(WHV)，它允许评估这类抗病毒药物在 首次建立了庚型肝炎病毒慢性感染动物模型。因此，我们在这个项目中建议 进行进一步的引线优化，并以最有利的ADME、安全和 体内白喉病毒感染土拨鼠体内抗病毒疗效研究的药代动力学(PK)谱。同时， 我们将继续努力了解BA抑制乙肝病毒的分子机制。 核衣壳组装及其对乙肝病毒与宿主相互作用的影响 肝细胞。在这个项目完成后，我们将更好地了解潜在的临床 单独或与核苷联合应用pgRNA靶向抗病毒治疗的益处 特别是类似物，以及对开发抗病毒疗法治疗慢性病的战略见解 乙肝病毒感染的总体情况。关于铅基础设施进一步临床前/临床发展的决定 化合物将相应地被制造出来。 项目摘要/摘要第7页