Approaches Towards Eradication of Hepatitis B Virus

描述(由申请人提供)： 摘要：目的：主要目的是确定清除乙肝病毒(乙肝病毒)储存库的策略，以允许终生停止抗乙肝治疗。我们将确定新的抗病毒药物和联合方法，通过干扰乙肝病毒核心蛋白浓度[CP]来靶向减少或消除cccDNA，这些药物与病毒聚合酶抑制剂一起可以为潜在的根除乙肝病毒提供临床前数据，从而消除终身慢性治疗的需要。研究计划：在两个肝细胞和一个新的原代细胞系统中测试新的异芳基二氢嘧啶(HAP)的聚焦文库，以寻找一种新的治疗剂来改变衣壳组装并破坏HBV共价闭合环状DNA(CccDNA)。这种新颖而原始的基于细胞的分析也可以用于筛选耐药病毒，这到目前为止还不可能。方法：我们发现了一种新型的针对乙肝病毒的无毒的纳米分子衣壳抑制剂，我们将对其进行进一步的评价和优化。我们还将设计和合成新的化学衍生物，测定它们的衣壳组装的物理化学性质以及由此引起的[CP]变化，并评估它们的体外细胞毒性、耐药谱、耐药突变选择、体内疗效和联合方案。临床意义：目前的口服抗乙肝治疗不能治愈，需要昂贵的终生治疗来抑制病毒。我们的新方法针对的是与病毒在乙肝病毒感染的肝细胞中持续存在相关的HBVcccDNA，潜在地消除了导致持续病毒学应答或治愈的主要的乙肝病毒储存库。

DESCRIPTION (provided by applicant): ABSTRACT: Objectives: The main objectives are to identify strategies to purge the hepatitis B virus (HBV) reservoir to permit the discontinuation of anti-HBV therapy for life. We will identify new antiviral agents and combined modalities to target reduction or elimination of cccDNA by disrupting HBV core protein concentration [Cp], which together with viral polymerase inhibitors could provide preclinical data towards the potential eradication of HBV, eliminating the need for lifetime chronic treatment. Research Plan: To test a focused library of novel heteroaryldihydropyrimidines (HAP) in both hepatic cells along with a novel primary cell system in search of a novel therapeutic agent to alter capsid assembly and disrupt HBV covalently closed-circular DNA (cccDNA). This novel and original cell based assay can also be used to select for resistant viruses, which until now has not been possible. Methods: We have discovered a novel non-toxic nanomolar capsid inhibitor for HBV that we will evaluate further and optimize. We will also design and synthesize novel chemical derivatives and determine their physico-chemical properties of capsid assembly as well as the resultant changes in [Cp], and assess their in vitro cytotoxicity, resistance profiles, selection for resistant mutations, and in ivo efficacy and in combination regimens. Clinical Relevance: Current oral anti-HBV therapy does not cure, requiring costly lifetime therapy to suppress virus. Our novel approaches target the HBV cccDNA that is associated with viral persistence in HBV-infected hepatocytes, potentially eliminating the major HBV reservoir leading to a sustained virological response or cure.