HBV Capsid Effectors

HBV衣壳效应器

• 批准号: 10454028
• 负责人: Raymond Felix Schinazi
• 金额: $ 63.57万
• 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: 2017-06-01 至 2022-03-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454028
• 关键词: Antiviral Agents; Area; Back; Binding; Biochemical; Biological; Biological Assay; Capsid; Cell Line; Cells; Chemicals; Chronic Hepatitis B; Circular DNA; Cirrhosis; Coin; Complex; Core Protein; DNA biosynthesis; Data; Development; Drug Kinetics; Electron Microscopy; Genetic Transcription; Goals; Hepatitis; Hepatitis B Surface Antigens; Hepatitis B Virus; Hepatitis B e Antigens; Hepatocyte; Homo; Human; Infection; Interferons; Kinetics; Label; Lead; Link; Liver; Malignant Neoplasms; Modality; Molecular Sieve Chromatography; Monitor; Morphology; Negative Staining; New Zealand; Pharmaceutical Preparations; Phase I Clinical Trials; Population; Primary carcinoma of the liver cells; Property; Proteins; Resistance; Resistance profile; Safety; Series; Site; Structure; Therapeutic; Toxic effect; United States National Institutes of Health; Vaccines; Viral; Virus; Virus Diseases; Virus Replication; Work; anti-hepatitis B; anti-viral efficacy; base; cytotoxicity; dimer; drug candidate; drug metabolism; epidemiologic data; experimental study; high risk; improved; in vivo; in vivo evaluation; innovation; life time cost; mouse model; mutant; novel; novel therapeutic intervention; nucleoside analog; particle; pgRNA; pre-clinical; preclinical study; prevent; programs; scale up; treatment duration; viral DNA; virus core

PROJECT SUMMARY/ABSTRACT Despite the availability of an effective vaccine, epidemiologic data estimates about 2 billion people globally are infected with hepatitis B virus (HBV). Approximately 350 million people are chronic HBV carriers and at high risk for the development of hepatitis, cirrhosis and hepatocellular carcinoma. Current anti-HBV treatment options suppress the virus but do not cure, requiring costly lifetime therapy. Thus, discovering and developing novel therapeutic approaches to not only suppress viral replication, but also eliminate HBV infection is key. Current approved therapeutic approaches fail to target the HBV covalently closed-circular DNA (cccDNA; associated with viral persistence) or the virus capsid which is essential for virus proliferation. Our innovative approach targets capsid assembly which is essential for replication, as DNA synthesis from cccDNA occurs exclusively within the capsid encoded particle. HBV core proteins (Cp) constitute the subunits in viral capsid assembly and Capsid Assembly Modulators (CAM) accelerate the kinetics of capsid assembly whereby they prevent pol-pgRNA complex encapsidation and block HBV replication. CAMs also interfere with cccDNA transcription/de novo formation during early steps of infection. As part of our ongoing HBV CAM discovery program NIH-supported over the last 5 years, we have been successful in developing several highly potent class II CAMs with one lead compound entering phase 1 clinical trials in October 2020. To advance the field and have back up compounds with improved profile, we recently identified several CAM homo- and hetero-dimer derivatives displaying anti- HBV activity in culture in the picomolar range. Because a dimeric structure linking two CAM moieties can interact with two distinct sites of one capsid or eventually connect two capsids together, we hypothesized that these compounds would have a more profound impact on HBV capsid assembly than known class I or II CAMs. Based on the potency and the unique mode of action of these compounds (which we call Class III), we propose to evaluate them by pursuing three specific aims: 1) To chemically optimize and characterize a unique series of CAM homo and heterodimers; 2) To structurally, biochemically, and biologically characterize novel CAM homo and heterodimers binding interaction with HBV capsid; 3) To determine pharmacokinetics and in vivo efficacy of novel CAM homo and heterodimers. Novel homo and heterodimers will be synthesized and evaluated to reach maximum potency and drug-like properties. To differentiate our compounds from existing class I and II CAMs, we will characterize structural and dynamical effects of our new CAMs by determining a) their effect on the morphology of HBV capsids and their localization within cells, b) binding to HBV wild type and known mutant Cp, c) resistance profile and activity against major CAM resistant HBV strains and d) intra- or inter-capsid connections. Results from the proposed studies will validate our novel class of CAM, which, when combined with other modalities could provide preclinical proof of concept towards a novel therapeutic strategy to eliminate HBV while reducing treatment duration and also eliminate progression to other complications.

项目摘要/摘要 尽管有有效的疫苗，但流行病学数据在全球范围内估计约20亿人 感染了丙型肝炎病毒（HBV）。大约3.5亿人是慢性HBV载体，高 肝炎，肝硬化和肝细胞癌的发展风险。当前的抗HBV治疗选择 抑制病毒，但不能治愈，需要昂贵的终身治疗。因此，发现和发展了新颖 治疗方法不仅可以抑制病毒复制，而且消除HBV感染是关键。当前的 批准的治疗方法无法靶向共价闭合DNA（CCCDNA；相关的） 病毒持久性）或病毒capsID对于病毒增殖至关重要。我们的创新方法目标 CAPSID组件对于复制至关重要，因为CCCDNA的DNA合成仅发生在 衣壳编码的粒子。 HBV核心蛋白（CP）构成病毒式衣壳组件和衣壳中的亚基 组装调节器（CAM）加速了衣壳组件的动力学，它们可以防止POL-PGRNA 复杂的封装和阻止HBV复制。凸轮也干扰CCCDNA转录/de从 在感染的早期步骤中形成。作为我们正在进行的HBV CAM发现计划NIH支持的一部分 在过去的五年中，我们成功地开发了几个具有领先优势的高强度II级凸轮 化合物于2020年10月进入1阶段临床试验。 有了改进的轮廓，我们最近确定了几个凸轮均和异二聚体衍生物，显示抗 皮摩尔范围内培养中的HBV活性。因为连接两个凸轮部分的二聚体结构可以相互作用 我们有两个不同的一个帽子或最终将两个衣壳连接在一起，我们假设这些 与已知的I类或II级凸轮相比，化合物对HBV帽固定组件的影响更大。基于 在这些化合物的效力和独特的作用方式上（我们称为III类），我们建议 通过追求三个具体目标来评估它们：1）化学优化和表征一系列独特的一系列 CAM HOMO和异二聚体； 2）在结构上，生化和生物学上表征新颖的CAM HOMO 和异二聚体与HBV衣壳结合相互作用； 3）确定药代动力学和体内功效 新颖的CAM HOMO和异二聚体。新颖的同性恋和异二聚体将被合成并评估以达到 最大效力和类似药物的特性。为了区分我们的化合物与现有的I类和II摄像头， 我们将通过确定a）对新凸轮的结构和动态效应来表征a）它们对 HBV衣壳的形态及其在细胞中的定位，b）与HBV野生型和已知突变体CP结合， c）电阻曲线和针对主要CAM耐药性HBV菌株和d）内部或capsid的活性 连接。拟议的研究的结果将验证我们的新型CAM类，当与之结合时 其他方式可以为消除HBV的新型治疗策略提供临床前的概念证明 同时减少治疗持续时间，并消除对其他并发症的发展。