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

联系人 PD/PI：郭巨涛 标题 乙型肝炎病毒核衣壳组装抑制剂的治疗效果评估 抽象的 这是一项确定新发现的苯甲酰胺的可行性和治疗益处的提案 衍生物（BA）作为单一治疗剂或与核苷类似物联合用于治疗 慢性乙型肝炎。BAs 在我们的实验室被鉴定为乙型肝炎病毒 (HBV) 前基因组的抑制剂 (pg) RNA 衣壳化，这对于随后的病毒 DNA 合成至关重要。他们机械地 与目前 FDA 批准的抗病毒药物不同，因此应该是其补充。此外， 抑制 pgRNA 衣壳化或核衣壳组装不仅应排除 HBV 基因组 复制和病毒颗粒的产生，它还可能破坏 HBV pgRNA 逆转录酶的代谢 (RT) 复合物和核心蛋白，可能会干扰宿主先天抗病毒免疫 受感染肝细胞中的反应和 cccDNA 功能。与其他 pgRNA 衣壳化抑制剂不同 迄今为止报道，我们的苯甲酰胺 pgRNA 衣壳化抑制剂也能有效抑制土拨鼠肝炎 病毒（WHV），它允许评估此类抗病毒药物的治疗效果 首次建立嗜肝DNA病毒慢性感染动物模型。因此，我们建议在这个项目中 进一步进行先导化合物优化，并开发具有最有利 ADME、安全性和 WHV 感染土拨鼠体内抗病毒功效研究的药代动力学 (PK) 曲线。同时， 我们将继续努力了解BAs抑制HBV的分子机制 核衣壳组装及其对 HBV 与其宿主之间相互作用的影响 肝细胞。该项目完成后，我们将更好地了解潜在的临床应用 pgRNA 衣壳化靶向抗病毒治疗（单独或与核苷联合治疗）的益处 特别是类似物，以及开发治疗慢性病的抗病毒方案的战略见解 一般乙型肝炎感染。关于先导 BA 进一步临床前/临床开发的决定 将相应地制备化合物。 项目总结/摘要第 7 页