HBV Capsid Effectors

项目摘要/摘要 乙肝病毒(乙肝病毒)仍然是全球公共卫生的主要挑战，有1000-2000万人 慢性感染者发展为肝硬变，以肝功能下降和丧失为特征 生活质量显著下降，死亡率高。虽然目前的治疗方法有效 控制病毒几乎没有副作用，他们不能治愈，因为没有一个目标的乙肝病毒共价关闭- 环状DNA(ccDNA；与病毒持久性有关)。我们的创新方法针对的是衣壳 组装，这是复制必不可少的，因为从cccDNA合成DNA只发生在 衣壳编码的粒子。因此，这项提议的重点是开发小分子 靶向干扰衣壳的形成，最终影响ccDNA的稳定性和/或形成 也缩短了乙肝病毒感染者的治疗时间。我们正在开发一种新型的 衣壳组装效应器(CAE)，靶向衣壳形成(乙草胺衍生物)。最近，我们 已经确定了一种高度有效的“先导”化合物IV，在3 nm处具有选择性活性。建议数 具体目标将系统地定义临床前参数(包括活性、毒性、稳定性、 口服生物利用度，衣壳结合相互作用)：目标1：化学优化 并表征了一系列独特的乙草胺CAE，包括我们的“先导”化合物IV；目标2：至 新型CAE与乙肝病毒结合作用的结构、生化和生物学特征 目的3：测定新型CAE及其配伍的药代动力学(PK)和疗效 治疗乙肝病毒感染的两种不同小鼠模型的治疗方案。这些研究的结果将验证我们的 一类新的小分子CAE，当与其他形式(例如，核苷)结合时 类似物)可以为一种新的治疗策略提供临床前的概念证明 治疗持续时间和对乙肝病毒感染的功能性治愈。

PROJECT SUMMARY / ABSTRACT Hepatitis B virus (HBV) remains a major worldwide public health challenge with 10-20 million chronically infected individuals developing cirrhosis, characterized by a decline and loss of liver function with a significantly decreased quality of life and a high mortality rate. While current therapies effectively control the virus with few side effects, they do not cure since none target the HBV covalently closed- circular DNA (cccDNA; associated with viral persistence). Our innovative approach targets capsid assembly which is essential for replication, as DNA synthesis from cccDNA occurs exclusively within the capsid encoded particle. Therefore, the focus of this proposal is on developing small molecules targeting disruption of capsid formation which could ultimately impact cccDNA stability and/or formation and also reduce duration of treatment in HBV infected persons. We are developing a novel class of Capsid Assembly Effectors (CAE) that target capsid formation (glyoxamide derivatives). Recently, we have identified a highly potent “lead” compound IV with selective activity at 3 nM. The proposed specific AIMS will systematically define the pre-clinical parameters (including activity, toxicity, stability, oral bioavailability, capsid binding interaction) of this novel class of CAE: AIM 1: to chemically optimize and characterize a unique series of glyoxamide CAE, including our “lead” compound IV; AIM 2: to structurally, biochemically, and biologically characterize novel CAE binding interaction with HBV capsid.; and AIM 3: to determine pharmacokinetics (PK) and efficacy of novel CAE and combination regimens in two different mouse models for HBV infection. Results from these studies will validate our novel class of small molecule CAE, which when combined with other modalities (e.g., nucleoside analogs) could provide preclinical “proof of concept” towards a novel therapeutic strategy with reduced treatment duration and a functional cure for HBV infection.