Evaluation of therapeutic benefits of HBV nucleocapsid assembly inhibitors

描述（由申请人提供）：这是一份确定新发现的苯酰胺衍生物（BAs）作为单一治疗剂或与核苷类似物联合治疗慢性乙型肝炎的可行性和治疗效果的提案。我们的实验室鉴定了BAs作为乙型肝炎病毒（HBV）基因组前RNA封装的抑制剂，这对随后的病毒DNA合成至关重要。它们在机制上不同于目前fda批准的抗病毒药物，因此应予以补充。此外，抑制pgRNA封装或核衣壳组装不仅可以阻止HBV基因组复制和病毒粒子产生，还可能破坏HBV pgRNA-逆转录酶（RT）复合物和核心蛋白的代谢，从而干扰宿主先天抗病毒免疫反应和感染肝细胞的cccDNA功能。与迄今为止报道的其他pgRNA封装抑制剂不同，我们的苯甲酰胺pgRNA封装抑制剂也能有效抑制土土鼠肝炎病毒（WHV），这允许在a中评估这类抗病毒药物的治疗益处

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.