Taking aim at HBV eradication using novel NRTIs and Capsid effectors

项目摘要 超过3.5亿人慢性感染B型肝炎病毒（HBV）， 发展成肝硬化和肝癌目前的药物不能治愈HBV，也不能靶向共价闭合的- 环状DNA（cccDNA），其与HBV感染的肝细胞中的病毒持久性有关。此外，委员会认为， 目前的治疗需要终生治疗以抑制病毒载量，并且延长的治疗导致 耐药菌株的发展。最后，只有一个家族的直接作用的抗逆转录病毒药物 （DAA）可以阻断HBV感染，阻止有意义的联合治疗， 高活性抗逆转录病毒疗法（HAART）在抗击艾滋病的斗争中发挥了重要作用。 这项工作的长期目标是开发导致HBV根除的HBV疗法。据推测 新的、有效的和选择性的HBV抑制剂的组合可以导致更有效的抑制 逆转录（RT）、缺乏交叉抗性、协同作用机制和cccDNA耗竭， 这反过来可能导致HBV的根除。为此，该项目侧重于开发 通过衣壳装配效应子（CAEs）和高效新型NRTI靶向病毒复制的先导物。的 建议的具体目标如下： 具体目标1：表征新型高活性NRTI的效力决定因素。 具体目标2：发现和表征新型衣壳组装效应子（CAEs） 具体目标3：新型NRTI和CAE组合的表征 这些研究将从两种不同的抗HBV药物中发现有希望的线索， 类，并将有助于设计新的组合，应有效地抑制cccDNA靶向Cp和 包括高度有效HBV NRTI，其朝向可导致HBV根除的持续病毒学应答。

PROJECT SUMMARY More than 350 million people are chronically infected by Hepatitis B Virus (HBV) and are at high risk for developing cirrhosis and liver cancer. Current drugs do not cure HBV and do not target covalently closed- circular DNA (cccDNA), which has been linked to viral persistence in HBV-infected hepatocytes. Moreover, current therapies require lifetime treatment to suppress viral load and prolonged treatments lead to the development of drug resistant strains. Finally, there is only a single family of directly acting antiretrovirals (DAAs) that can block HBV infection, preventing meaningful combination therapies equivalent to formidable highly active antiretroviral therapies (HAART) that tipped the scales in the fight against AIDS. The long term goal of this work is to develop HBV therapies that lead to HBV eradication. It is hypothesized that combinations of novel, potent, and selective inhibitors of HBV can lead to more efficient suppression of reverse transcription (RT), lack of cross-resistance, synergistic mechanism of action and depletion of cccDNA, which in turn could lead to the eradication of HBV. Towards that end, this project focuses on the development of leads that target viral replication by capsid assembly effectors (CAEs) and highly potent novel NRTIs. The following specific aims are proposed: Specific Aim 1: Characterize the potency determinants of novel highly active NRTIs. Specific Aim 2: Discovery and characterization of novel capsid assembly effectors (CAEs) Specific Aim 3: Characterization of novel NRTI and CAE combinations These studies will identify promising leads for the development of future anti-HBV drugs from two different classes and will help design novel combinations that should efficiently suppress cccDNA by targeting Cp and include highly potent HBV NRTIs towards a sustained virological response that could lead to HBV eradication.