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: 8850811
• 负责人: Yanming Du
• 金额: $ 66.97万
• 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/8850811
• 关键词: Animal Model; Antiviral Agents; Antiviral Response; Antiviral Therapy; Benzamides; Biological; Biological Availability; Capsid; Capsid Proteins; Chemicals; Chronic Hepatitis B; Circular DNA; Clinical; Combined Modality Therapy; Complement; Complex; Core Protein; DNA Polymerase Inhibitor; DNA biosynthesis; DNA-Directed DNA Polymerase; Development; Drug Kinetics; Excretory function; FDA approved; Goals; Health; Hepadnaviridae; Hepatitis B; Hepatitis B Virus; Hepatocyte; Human; Immune; Immune response; In Vitro; Kinetics; Knowledge; Laboratories; Late Effects; Lead; Maximum Tolerated Dose; Metabolism; Modification; Molecular; Mono-S; Mus; Nucleocapsid; Pathway interactions; Pharmaceutical Preparations; Process; Production; RNA; RNA-Directed DNA Polymerase; Reporting; Research; Resistance; Safety; Testing; Therapeutic; Therapeutic Agents; Time; Transcriptional Regulation; Viral; Viral Genome; Virion; Virus Replication; Woodchuck; Woodchuck Hepatitis B Virus; Work; absorption; cytotoxicity; design; drug candidate; entecavir; hepatoma cell; in vivo; inhibitor/antagonist; insight; mutant; nucleoside analog; pgRNA; pre-clinical; response; scale up; therapeutic evaluation; viral DNA; virus host interaction

DESCRIPTION (provided by applicant): 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.

描述（由申请方提供）：这是一项旨在确定新发现的苯甲酰胺衍生物（BA）作为单一治疗药物或与核苷类似物联合治疗慢性乙型肝炎B的可行性和治疗获益的提案。在我们的实验室中，BAs被鉴定为对B型肝炎病毒（HBV）前基因组（pg）RNA合成的抑制剂，这对于随后的病毒DNA合成是必需的。它们在机制上与目前FDA批准的抗病毒药物不同，因此应该是它们的补充。此外，抑制pgRNA聚合或核衣壳组装不仅应阻止HBV基因组复制和病毒体产生，还可能破坏HBV pgRNA-逆转录酶（RT）复合物和核心蛋白的代谢，从而干扰宿主先天性抗病毒免疫应答和感染肝细胞中cccDNA的功能。与迄今为止报道的其他pgRNA糖苷化抑制剂不同，我们的苯甲酰胺pgRNA糖苷化抑制剂还有效地抑制土拨鼠肝炎病毒（WHV），这允许在临床上评估这类抗病毒药的治疗益处。 嗜肝DNA病毒慢性感染动物模型。因此，我们建议在本项目中进行进一步的铅优化，并推进具有最有利的ADME，安全性和药代动力学（PK）特征的化合物，用于体内WHV感染土拨鼠的抗病毒疗效研究。同时，我们将继续努力了解BA抑制HBV核衣壳组装的分子机制及其对HBV与宿主肝细胞相互作用的影响。在该项目完成后，我们将更好地了解pgRNA靶向抗病毒治疗的潜在临床益处，无论是单独使用还是与核苷类似物联合使用， 和战略见解的发展抗病毒治疗慢性肝炎 一般来说是B类感染。将相应地做出关于先导BA化合物的进一步临床前/临床开发的决定。