权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

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。