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（由申请人提供）：这是确定新发现的苯甲酰胺衍生物（BAS）作为单疗法剂的可行性和治疗益处的建议，或者与核苷类似物结合使用核苷类似物，用于治疗慢性乙型肝炎B的BAS B bas B BAS在我们的实验室中鉴定为hepatiation senta is eent基因抑制剂（HEBV）。随后的病毒DNA合成。它们在机械上与当前FDA批准的抗病毒药物相反，因此应补充。 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.与迄今为止报道的其他PGRNA封装抑制剂不同，我们的苯甲胺PGRNA封装抑制剂也有效地抑制了Woodchuck肝炎病毒（WHV），这允许评估该类别的抗病毒药物在A中的治疗益处 肝病病毒首次长期感染动物模型。因此，我们建议在该项目中进行进一步的铅优化，并具有最有利的ADME，安全性和药代动力学（PK）特征，以在Vivo的WHV感染的Woodchuck中进行抗病毒功效研究。同时，我们将继续努力理解BAS抑制HBV Nucleocapsid组装及其对HBV及其宿主肝细胞相互作用的结果影响的分子机制。该项目完成后，我们将更好地了解PGRNA封装为靶向的抗病毒疗法的潜在临床益处，无论是单独还是与核苷类似物结合使用， 以及为治愈慢性肝炎的抗病毒制度发展的战略见解 B通常感染。将对铅BAS化合物的进一步临床前/临床开发做出决定。