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：
10081385
负责人：
Zachary David Aron
金额：
$ 29.85万
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 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10081385
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：丙型肝炎病毒（HBV）是一种小型DNA病毒，在全球范围内长期感染了2.4亿人每年导致超过65万人死亡。 HBV诱发的死亡通常是由各种严重的肝病，包括肝硬化，肝细胞癌和肝衰竭。慢性HBV感染的当前护理标准使用病毒DNA聚合酶抑制剂或免疫调节剂（干扰素）可减少病毒载荷并防止肝脏进展疾病，但很少诱导功能性治疗，复发几乎普遍发生停止治疗后。无法实现功能治疗的无法归因于在感染的肝细胞中，病毒式闭合圆形DNA（CCCDNA）池的持久性这些疗法既没有被抑制也没有抑制。彼此之间，对新的迫切需要针对病毒生命周期的多个阶段的HBV疗法可能影响这些CCCDNA 游泳池。我们发现了一种新型的HBV核心蛋白质变构调节剂（CPAM），由MBX-6035举例说明，该MBX-6035通过独特的表型破坏了衣壳组件。分析 MBX-6035类似物显示出响应性的SAR，并包括潜在的类似物（EC50为低 AS 1.3 µm），选择性（> 100倍SI），固体（最大400 µm），最小蛋白质结合（> 30％）在鼠血浆中未结合）和代谢稳定（鼠肝微粒体中的T1/2> 100分钟），强烈地证明了这一新系列的进一步追求。我们在此阶段的策略是优化该系列的效力和类似药物样特性，以生成合适的铅化合物为了进一步开发和证明未来II期应用中体内效率。