Development of a New Class of Hepatitis B Virus Inhibitors that Induce a Novel Defective Nucleocapsid Phenotype

摘要： 乙肝病毒是一种小型DNA病毒，慢性感染全球2.4亿人， 每年造成超过65万人死亡。由乙肝病毒引起的死亡通常是由 各种严重的肝脏病理，包括肝硬变、肝细胞癌和肝功能衰竭。 目前治疗慢性乙肝病毒感染的标准是使用病毒DNA聚合酶抑制剂或 免疫调节剂(干扰素)，可降低病毒载量并防止肝脏恶化 疾病，但很少能导致功能性治愈，复发几乎普遍发生 在停止治疗后。未能实现功能性治愈归因于 病毒共价闭合环状DNA(CccDNA)池在感染肝细胞中的持久性 这些疗法既没有抑制也没有消除。因此，迫切需要新的 针对病毒生命周期多个阶段的乙肝治疗药物可以影响这些cccDNA 泳池。我们发现了一种新型的乙肝核心蛋白变构调节剂(CPAM)， 以MBX-6035为例，它通过一种独特的表型破坏衣壳组装。分析 MBX-6035类似物显示出响应的SAR，并包括功能强大的类似物(EC50为低 作为1.3微米)，选择性(&gt；100倍SI)，可溶(高达400微米)，最低蛋白质结合(&gt；30% 在小鼠血浆中无结合)，代谢稳定(在小鼠肝微粒体中为T1/2&gt；100min)， 有力地证明了进一步追求这一系列小说的合理性。我们在此第一阶段提案中的策略是 优化该系列的效力和类药物特性，以产生合适的先导化合物 用于在未来的第二阶段应用中进一步开发和展示体内疗效。

Summary: Hepatitis B virus (HBV) is a small DNA virus that chronically infects 240 million people worldwide, resulting in over 650 thousand deaths annually. HBV-induced fatalities typically result from a variety of severe liver pathologies including cirrhosis, hepatocellular carcinoma and liver failure. The current standard of care for chronic HBV infection uses viral DNA polymerase inhibitors or immunomodulators (interferons) that reduces viral loads and prevents progression of liver disease, but rarely induces a functional cure, with recurrence occurring nearly universally following cessation of treatment. The failure to achieve a functional cure is attributed to the persistence of viral covalently closed circular DNA (cccDNA) pools in infected liver cells that is neither suppressed nor eliminated by these therapies. Accordingly, there is a critical need for new HBV therapeutics targeting multiple stages of the viral lifecycle which can affect these cccDNA pools. We have discovered a new Type of HBV core protein allosteric modulators (CpAMs), exemplified by MBX-6035, that disrupt capsid assembly through a unique phenotype. Analysis of MBX-6035 analogs revealed responsive SAR and included analogs that are potent (EC50 as low as 1.3 µM), selective (>100-fold SI), soluble (up to 400 µM), minimally protein bound (>30% unbound in murine plasma), and metabolically stable (t1/2 >100 min in murine liver microsomes), strongly justifying further pursuit of this novel series. Our strategy in this Phase I proposal is to optimize the potency and drug-like properties of this series to generate lead compounds suitable for further development and demonstration of in vivo efficacy in a future Phase II application.