Taking aim at HBV eradication using novel NRTIs and Capsid effectors

使用新型 NRTI 和衣壳效应物消灭 HBV

• 批准号: 9918244
• 负责人: Stefan G Sarafianos
• 金额: $ 56.87万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-11-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918244
• 关键词: 2' -deoxyadenosine; Acquired Immunodeficiency Syndrome; Address; Anti-Retroviral Agents; Antiviral Agents; Biological Assay; Capsid; Catabolism; Cell Line; Cells; Chronic; Circular DNA; Cirrhosis; Clinical Markers; Combined Modality Therapy; Core Protein; Crystallization; Crystallography; DNA; Data; Deoxyguanosine; Development; Drug Targeting; Family; Future; Goals; Group Structure; HIV; HIV drug resistance; Hepatitis B; Hepatitis B Therapy; Hepatitis B Virus; Hepatitis B e Antigens; Hepatitis C virus; Hepatocyte; Hepatology; Highly Active Antiretroviral Therapy; Immunofluorescence Immunologic; Individual; Laboratories; Lead; Life Cycle Stages; Link; Maintenance; Malignant neoplasm of liver; Methods; Molecular; Monitor; Multi-Drug Resistance; Nuclear; Nucleocapsid; Nucleosides; Patients; Pharmaceutical Preparations; Polymerase; Publications; Publishing; RNA; Resistance; Reverse Transcriptase Inhibitors; Reverse Transcription; Role; Structure; Structure-Activity Relationship; Time; Vaccines; Viral; Viral Load result; Viral Proteins; Virus; Virus Diseases; Virus Receptors; Virus Replication; Western Blotting; Work; anti-hepatitis B; base; clinical development; clinically relevant; cytotoxicity; deoxyguanosine triphosphate; design; drug development; entecavir; experience; fight against; high risk; inhibitor/antagonist; insight; molecular modeling; novel; novel therapeutics; overexpression; pgRNA; polymerization; prevent; protein expression; public health relevance; resistant strain; response; synergism; therapy development; treatment response; tripolyphosphate; viral DNA; viral RNA; virology

PROJECT SUMMARY More than 350 million people are chronically infected by Hepatitis B Virus (HBV) and are at high risk for developing cirrhosis and liver cancer. Current drugs do not cure HBV and do not target covalently closed- circular DNA (cccDNA), which has been linked to viral persistence in HBV-infected hepatocytes. Moreover, current therapies require lifetime treatment to suppress viral load and prolonged treatments lead to the development of drug resistant strains. Finally, there is only a single family of directly acting antiretrovirals (DAAs) that can block HBV infection, preventing meaningful combination therapies equivalent to formidable highly active antiretroviral therapies (HAART) that tipped the scales in the fight against AIDS. The long term goal of this work is to develop HBV therapies that lead to HBV eradication. It is hypothesized that combinations of novel, potent, and selective inhibitors of HBV can lead to more efficient suppression of reverse transcription (RT), lack of cross-resistance, synergistic mechanism of action and depletion of cccDNA, which in turn could lead to the eradication of HBV. Towards that end, this project focuses on the development of leads that target viral replication by capsid assembly effectors (CAEs) and highly potent novel NRTIs. The following specific aims are proposed: Specific Aim 1: Characterize the potency determinants of novel highly active NRTIs. Specific Aim 2: Discovery and characterization of novel capsid assembly effectors (CAEs) Specific Aim 3: Characterization of novel NRTI and CAE combinations These studies will identify promising leads for the development of future anti-HBV drugs from two different classes and will help design novel combinations that should efficiently suppress cccDNA by targeting Cp and include highly potent HBV NRTIs towards a sustained virological response that could lead to HBV eradication.

项目概要 超过 3.5 亿人长期感染乙型肝炎病毒 (HBV)，并且处于感染乙型肝炎病毒的高风险中 发展为肝硬化和肝癌。目前的药物不能治愈乙肝病毒，也不能靶向共价闭合- 环状 DNA (cccDNA)，与 HBV 感染的肝细胞中病毒的持续存在有关。而且， 目前的疗法需要终生治疗以抑制病毒载量，长期治疗会导致 耐药菌株的发展。最后，只有一个直接作用的抗逆转录病毒药物家族 （DAA）可以阻断 HBV 感染，防止有意义的联合疗法相当于强大的 高效抗逆转录病毒疗法 (HAART) 扭转了抗击艾滋病的局面。 这项工作的长期目标是开发能够根除 HBV 的 HBV 疗法。据推测 新型、强效、选择性的 HBV 抑制剂的组合可以更有效地抑制 逆转录 (RT)、缺乏交叉耐药性、协同作用机制和 cccDNA 耗尽， 这反过来又可能导致乙肝病毒的根除。为此，该项目的重点是开发 通过衣壳组装效应器 (CAE) 和高效新型 NRTI 靶向病毒复制的先导化合物。这 提出以下具体目标： 具体目标 1：表征新型高活性 NRTI 的效力决定因素。 具体目标 2：新型衣壳组装效应器 (CAE) 的发现和表征 具体目标 3：新型 NRTI 和 CAE 组合的表征 这些研究将从两种不同的药物中找出未来抗乙型肝炎药物开发的有希望的线索。 类，将有助于设计新颖的组合，通过靶向 Cp 和 包括高效的 HBV NRTI，以实现持续的病毒学反应，从而导致 HBV 根除。

项目成果

Discovery of New Small Molecule Hits as Hepatitis B Virus Capsid Assembly Modulators: Structure and Pharmacophore-Based Approaches.

• DOI: 10.3390/v13050770
• 发表时间: 2021-04-27
• 期刊: Viruses
• 作者: Senaweera S;Du H;Zhang H;Kirby KA;Tedbury PR;Xie J;Sarafianos SG;Wang Z
• 通讯作者: Wang Z