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.

项目总结 超过3.5亿人慢性感染乙肝病毒(乙肝病毒)，并处于 发展为肝硬变和肝癌。目前的药物不能治愈乙肝病毒，也不针对共价封闭的- 环状DNA(CcDNA)，已被认为与病毒在乙肝病毒感染的肝细胞中的持久性有关。此外， 目前的治疗方法需要终生治疗以抑制病毒载量，而延长治疗时间会导致 耐药菌株的开发。最后，只有一类直接作用的抗逆转录病毒药物。 (DaaS)可以阻止乙肝病毒感染，防止有意义的联合疗法，相当于令人敬畏 高效抗逆转录病毒疗法(HAART)在抗击艾滋病方面起到了举足轻重的作用。 这项工作的长期目标是开发能够根除乙肝病毒的乙肝治疗方法。这是假设的 新的、有效的和选择性的乙肝病毒抑制剂的组合可以导致更有效的抑制 逆转录(RT)，缺乏交叉抗性，协同作用机制和耗竭的cccDNA， 这反过来可能导致根除乙肝病毒。为此，本项目的重点是开发 通过衣壳组装效应器(CAE)和高度有效的新型核转录因子(NRTI)靶向病毒复制的多个线索。这个 提出了以下具体目标： 具体目标1：表征新型高活性NRTI的效力决定因素。 特定目标2：发现和表征新型衣壳组装效应器(CAE) 具体目标3：新的NRTI和CAE组合的特征 这些研究将从两个不同的角度为未来抗乙肝药物的开发确定有希望的线索 类，并将有助于设计新的组合，通过靶向CP和CcDNA来有效地抑制ccDNA 包括高度有效的HBVNRTIs，以实现可导致根除HBV病毒的持续病毒学反应。

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