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.

项目摘要 超过3.5亿人因乙型肝炎病毒（HBV）长期感染，并且有高风险 发展肝硬化和肝癌。目前的药物无法治愈HBV，也不靶向共价闭合 - 圆形DNA（CCCDNA），与HBV感染的肝细胞中的病毒持久性有关。而且， 当前的疗法需要终生治疗以抑制病毒负荷，并长期治疗导致 抗药性菌株的发展。最后，只有一个直接作用抗逆转录病毒的家族 （DAA）可以阻止HBV感染，防止有意义的组合疗法等效于强大 高度活跃的抗逆转录病毒疗法（HAART）在与艾滋病的斗争中倾斜了尺度。 这项工作的长期目标是开发导致消除HBV的HBV疗法。它是假设的 新颖，有效和选择性抑制剂的组合可以导致更有效地抑制 逆转录（RT），缺乏交叉耐药性，作用的协同机理和CCCDNA的消耗， 这反过来可能导致根除HBV。为此，该项目着重于发展 用衣壳装配效应子（CAE）和高度有效的新型NRTI靶向病毒复制的潜在客户。这 提出了以下特定目标： 特定目标1：表征新型高度活性NRTI的效力决定因素。 特定目的2：新型衣壳组装效应子（CAE）的发现和表征 特定目标3：新型NRTI和CAE组合的表征 这些研究将确定有希望的潜在客户，以开发从两种不同的未来抗HBV药物开发 课程并将有助于设计新型组合，应通过针对CP和 包括高度有效的HBV NRTI，对可能导致HBV消除的持续病毒学反应。

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