HBV Capsid Effectors

HBV衣壳效应器

• 批准号: 10446725
• 负责人: Raymond Felix Schinazi
• 金额: $ 43.79万
• 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 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446725
• 关键词: Antigens; Area; Binding; Biochemical; Biological Assay; Capsid; Cell Line; Cells; Chemicals; Chronic Hepatitis B; Circular DNA; Cirrhosis; Clinical Research; Coin; Complex; Core Protein; DNA biosynthesis; Data; Development; Drug Kinetics; FDA approved; Genetic Transcription; Goals; Hepatitis; Hepatitis B Infection; Hepatitis B Surface Antigens; Hepatitis B Virus; Hepatitis B e Antigens; Hepatocyte; Homo; Human; Immunofluorescence Immunologic; In Vitro; Infection; Interferons; Kinetics; Lead; Link; Modality; Monitor; Morphology; Negative Staining; Persons; Pharmaceutical Preparations; Phase I Clinical Trials; Phase Ib Clinical Trial; Population; Primary carcinoma of the liver cells; Property; Proteins; Regimen; Resistance; Resistance profile; Safety; Series; Site; Structure; Therapeutic; Time; Toxic effect; Transmission Electron Microscopy; 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; high risk; in vivo; in vivo evaluation; inhibitor; innovation; life time cost; light scattering; monomer; 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 (HCC). Current anti-HBV treatment options suppress the virus but do not eliminate the virus, requiring costly lifetime therapy. All FDA 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 approach in this application is to target 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 4 years, we have been successful in developing several highly potent (sub-micromolar) class II CAMs with one of our lead compounds entering phase 1 clinical trials in October 2020. However, there are numerous hurdles that could derail our efforts towards FDA approval. Here, we describe for the first time a novel class of homo or hetero-dimer CAM displaying selective 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 (or more) 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 (MoA) we termed our new compounds as “class III” CAMs. We propose to evaluate these class III CAMs by pursuing three specific aims: 1) To chemically optimize and characterize a unique series of CAM homo/heterodimers made from novel monomers; 2) To characterize (structurally, biochemically, and biologically) novel CAM homo/heterodimer binding interaction with HBV capsid; 3) To determine pharmacokinetics (PK) 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 III CAM, which, when combined with other modalities will provide pre-clinical proof of concept towards a novel therapeutic strategy to eliminate HBV while reducing treatment duration and progression to HCC.

项目总结/摘要 尽管有效的疫苗已经问世，但流行病学数据估计，全球约有20亿人感染了艾滋病毒。 感染了B型肝炎病毒（HBV）。大约3.5亿人是慢性HBV携带者， 发生肝炎、肝硬化和肝细胞癌（HCC）的风险。目前的抗HBV治疗 选择抑制病毒，但不能消除病毒，需要昂贵的终身治疗。所有FDA批准的 治疗方法未能靶向HBV共价闭合环状DNA（cccDNA;与病毒相关， 持久性）或病毒增殖所必需的病毒衣壳。我们在此应用程序中的方法是 靶向衣壳组装，这是复制所必需的，因为仅发生从cccDNA的DNA合成 在衣壳编码的颗粒内。HBV核心蛋白（Cp）构成病毒衣壳装配中的亚单位， 衣壳组装调节剂（CAM）加速衣壳组装的动力学，从而它们防止多聚化。 pgRNA复合物抑制并阻断HBV复制。CAM还干扰cccDNA转录/表达。 在感染的早期阶段新生形成。作为我们正在进行的HBV CAM发现计划NIH的一部分- 在过去4年的支持下，我们成功开发了几种高效（亚微摩尔） II类CAM，我们的一种先导化合物于2020年10月进入1期临床试验。但 有很多障碍会阻碍我们获得FDA的批准在这里，我们第一次描述了一个 一类新的同源或异源二聚体CAM，其在皮摩尔范围的培养物中显示出选择性抗HBV活性。 因为连接两个CAM部分的二聚体结构可以与一个衣壳的两个不同位点相互作用， 最终将两个（或更多）衣壳连接在一起，我们假设这些化合物将具有更多的 比已知的I类或II类CAM对HBV衣壳组装有更深刻的影响。基于它的效力和独特性 我们将我们的新化合物称为“III类”CAM。我们建议评估这些类 III CAM通过追求三个具体目标：1）化学优化和表征一系列独特的CAM 由新单体制成的同/异二聚体; 2）表征（结构、生化和生物学） 新的CAM同/异二聚体与HBV衣壳的结合相互作用; 3）确定药代动力学（PK）和 新CAM同源和异源二聚体的体内功效。将合成新的同源和异源二聚体， 评估以达到最大效力和药物样性质。将我们的化合物与现有的 I类和II类CAM，我们将通过确定a） 它们对HBV衣壳形态及其在细胞内定位的影响，B）与HBV野生型结合， 已知突变Cp，c）对主要CAM耐药HBV毒株的耐药谱和活性，和d）体内或 衣壳间连接。从拟议的研究结果将验证我们的新的III类CAM，当 与其他方式相结合将为新的治疗策略提供临床前概念验证， 消除HBV，同时减少治疗时间和进展为HCC。