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

开发一类新型乙型肝炎病毒抑制剂，可诱导新型缺陷核衣壳表型

基本信息

批准号：
10220712
负责人：
Zachary David Aron
金额：
$ 29.83万
依托单位：
MICROBIOTIX, INC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-21 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10220712
关键词：
Affect Antiviral Agents Automobile Driving Binding Binding Proteins Biological Assay Biological Markers Capsid Capsid Proteins Cell Line Cells Cessation of life Characteristics Chronic Chronic Hepatitis B Circular DNA Cirrhosis Clinical Trials Combined Modality Therapy Core Protein DNA Polymerase Inhibitor DNA Viruses DNA biosynthesis DNA-Directed DNA Polymerase DNA-Directed RNA Polymerase Development Dose Drug Kinetics Evaluation Exhibits Failure Future Goals Hepatitis B Virus Hepatocyte Hydrophobicity Immunomodulators In Vitro Interferons Lead Libraries Life Cycle Stages Liver Liver Failure Liver Microsomes Liver diseases Maintenance Mammalian Cell Metabolic Monitor Mus Nucleocapsid Oral Pathology Permeability Pharmaceutical Preparations Pharmacology Phase Phenotype Plasma Play Polymers Primary carcinoma of the liver cells Property RNA Recurrence Replicon Resistance profile Series Serum Solubility Testing Viral Viral Load result Virus Inhibitors Withholding Treatment Work analog aqueous base cytotoxicity design dimer entecavir improved in vivo inhibitor/antagonist interest mouse model mutant novel pre-clinical prevent programs protein folding standard of care therapeutic target viral DNA

项目摘要

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.

概括：乙型肝炎病毒 (HBV) 是一种小型 DNA 病毒，长期感染全球 2.4 亿人，每年导致超过 65 万人死于 HBV 引起的死亡。各种严重的肝脏病变，包括肝硬化、肝细胞癌和肝功能衰竭。目前慢性 HBV 感染的护理标准使用病毒 DNA 聚合酶抑制剂或免疫调节剂（干扰素）可减少病毒载量并防止肝脏进展疾病，但很少能实现功能性治愈，几乎普遍会出现复发停止治疗后未能实现功能性治愈的原因是：病毒共价闭合环状 DNA (cccDNA) 库在受感染的肝细胞中持续存在，这些疗法既不能抑制也不能消除。因此，迫切需要新的疗法。针对病毒生命周期多个阶段的 HBV 疗法可影响这些 cccDNA 我们发现了一种新型 HBV 核心蛋白变构调节剂 (CpAM)，以 MBX-6035 为例，它通过独特的表型分析破坏衣壳组装。 MBX-6035 类似物显示出响应性 SAR，并包含有效的类似物（EC50 低）为 1.3 µM）、选择性（>100 倍 SI）、可溶（高达 400 µM）、最低限度的蛋白质结合（>30% 在小鼠血浆中未结合），且代谢稳定（在小鼠肝微粒体中 t1/2 >100 分钟），强烈证明我们在第一阶段提案中的进一步追求是合理的。优化该系列的效力和类药特性以产生适合先导的化合物在未来的 II 期应用中进一步开发和证明体内功效。