Discovery of inhibitors that target HBx for the treatment of chronic HBV infection

发现针对 HBx 的抑制剂用于治疗慢性 HBV 感染

• 批准号: 10155986
• 负责人: Glen Andrew Coburn
• 金额: $ 25.28万
• 依托单位: VENATORX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10155986
• 关键词: Acute; Adult; Alanine Transaminase; Antibodies; Antiviral Agents; Automobile Driving; Binding; Biological Assay; Chromosomes; Chronic; Chronic Hepatitis B; Cirrhosis; Collaborations; Complex; DNA biosynthesis; DNA-Binding Proteins; Development; Disease Progression; Dose; Drug Kinetics; Drug Targeting; Evaluation; Exhibits; Feasibility Studies; Funding; Gene Expression; Gene Silencing; Genetic Transcription; Goals; Hepatitis; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B Virus; Hepatitis B X-Protein; Hepatocyte; Histologic; Host Defense Mechanism; Human; Immune; Individual; Infection; Integration Host Factors; Interferon-alpha; Investigation; Lead; Libraries; Life; Liver; Liver Cirrhosis; Liver diseases; Luciferases; Maintenance; Molecular Target; Oral; Pathway interactions; Perinatal Exposure; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Play; Primary carcinoma of the liver cells; Property; Publishing; Reverse Transcriptase Inhibitors; Risk; Role; Series; Signal Transduction; Small Business Innovation Research Grant; Structure-Activity Relationship; System; Technology; Tenofovir; Testing; UV induced DNA damage; Ubiquitination; Vaccines; Vertical Disease Transmission; Viral; Viral Genes; Viral Regulatory Proteins; Virus Diseases; Virus Inhibitors; Virus Replication; analog; candidate selection; counterscreen; cytotoxicity; drug discovery; early childhood; entecavir; extrachromosomal DNA; high throughput screening; immunoregulation; improved; indexing; inhibitor/antagonist; lead optimization; lead series; novel; prevent; programs; recruit; response; seroconversion; small molecule; small molecule libraries; success; ubiquitin-protein ligase; viral DNA

PROJECT SUMMARY The HBV X protein (HBx) represents an attractive target for drug discovery efforts as it plays a central role in activating viral gene expression and promoting conditions that allow the cccDNA form of HBV to persist in the hepatocytes of chronically infected individuals. The objective of this Phase I SBIR feasibility study is to identify drug-like compounds that selectively inhibit a key interaction between HBx and a host factor DDB1 (UV damaged DNA binding protein 1) that is responsible for activating transcription from the cccDNA template. During the course of this Phase I funding period, we will execute a hit finding campaign against a library of 200,000 compounds with optimal drug-like properties. Quality hits that emerge from the assay will be subjected to follow-on testing that will investigate the potency, selectivity, and mechanism of action. The most interesting of these compounds will be subjected to medicinal chemistry driven hit-to-lead to explore structure-activity relationships (SAR). The overall goal of this project is to discover one or more novel lead series which is defined as a chemotype inhibitor that demonstrates tractable SAR, potent antiviral activity against HBV and minimal cytotoxicity. Success in these endeavors will trigger the submission of a Phase II application that will advance the program from Early Lead Optimization through to Candidate Selection.

项目摘要 HBV X蛋白（HBX）代表了药物发现工作的有吸引力的目标，因为它在 激活病毒基因表达和促进条件，使CCCDNA形式的HBV持续存在 长期感染个体的肝细胞。该阶段I SBIR可行性研究的目的是确定 类似药物的化合物，可有选择地抑制HBX和宿主因子DDB1之间的关键相互作用（UV 受损的DNA结合蛋白1）负责从CCCDNA模板激活转录。 在此阶段I资金期间，我们将针对 200,000种具有最佳药物样特性的化合物。从测定法中出现的质量命中将受到进行 跟进测试将研究效力，选择性和作用机理。最有趣的 这些化合物将受到药物化学驱动的命中率，以探索结构活性 关系（SAR）。该项目的总体目标是发现一个或多个新颖的潜在客户系列 定义为表现出可易处理的SAR的化学型抑制剂，针对HBV的有效抗病毒活性和 最小的细胞毒性。在这些努力中的成功将触发II期应用程序的提交 将程序从早期铅优化到候选人选择提高。