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

总结： B型肝炎病毒（HBV）是一种小的DNA病毒，在全世界慢性感染2.4亿人， 导致每年超过65万人死亡。HBV引起的死亡通常是由于 各种严重肝脏病理，包括肝硬化、肝细胞癌和肝功能衰竭。 目前慢性HBV感染的标准治疗使用病毒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疾病进展 疾病，但很少引起功能性治愈，复发几乎普遍发生 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）池在感染的肝细胞中的持续存在， 既不被这些疗法抑制也不被消除。因此，迫切需要新的 HBV治疗剂靶向病毒生命周期的多个阶段，可影响这些cccDNA 池.我们发现了一种新型的HBV核心蛋白变构调节剂（CpAMs）， 例如MBX-6035，其通过独特的表型破坏衣壳组装。分析 MBX-6035类似物显示出响应性SAR，并且包括有效的类似物（EC 50低 作为1.3 µM），选择性（>100倍SI），可溶性（高达400 µM），最低蛋白结合（>30% 在鼠血浆中未结合），并且代谢稳定（在鼠肝微粒体中t1/2 >100 min）， 这是对这部小说系列的进一步追求。我们在第一阶段建议中的策略是 优化该系列的效力和药物样性质以产生适合的先导化合物 用于在未来的II期应用中进一步开发和证明体内功效。

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.