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.

项目摘要/摘要 尽管有有效的疫苗可用，但流行病学数据估计全球约有20亿人 感染了乙肝病毒(乙肝病毒)。约有3.5亿人是慢性乙肝病毒携带者，而且处于高发期 有患肝炎、肝硬变和肝细胞癌的风险。目前的抗-HBs治疗 选择抑制病毒但不能消除病毒，需要昂贵的终生治疗。所有FDA都批准了 治疗方法不能靶向乙肝病毒共价闭合环状DNA(cccDNA；与病毒相关 持久性)或对病毒增殖至关重要的病毒衣壳。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，因为从cccDNA合成DNA是专门发生的 在衣壳编码的粒子中。乙型肝炎病毒核心蛋白(CP)构成病毒衣壳组装的亚单位，并 衣壳组装调节剂(CAM)加速衣壳组装的动力学，从而防止极化- PgRNA复合体包裹，阻断乙肝病毒复制。CAM也干扰cccDNA的转录/降解 在感染的早期阶段形成新的病毒。作为我们正在进行的HBVCAM发现计划的一部分，NIH- 在过去四年的支持下，我们已经成功地开发出了几种高效的(亚微磨牙) 我们的一种先导化合物将于2020年10月进入第一阶段临床试验。然而，在那里 有许多障碍可能会破坏我们争取FDA批准的努力。在这里，我们首次描述了一种 一种新型的同源或异源二聚体CAM，在皮摩尔范围内的培养中显示选择性的抗乙肝病毒活性。 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的位置相互作用 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有更多 比已知的I类或II类凸轮对乙肝病毒衣壳组装的影响更深。基于效力和独特性 作用模式(MOA)我们把我们的新化合物命名为“III类”凸轮。我们建议对这些班级进行评估 III凸轮通过追求三个具体目标：1)在化学上优化和表征一系列独特的凸轮 由新型单体制成的同/异二聚体；2)表征(结构、生物化学和生物) 新的CAM同/异二聚体与乙肝病毒衣壳的结合作用；3)测定药代动力学(PK)和 新型CAM同源和异源二聚体的体内疗效。将合成新型同源和杂化二聚体，并 评估以达到最大效力和类似药物的特性。将我们的化合物与现有的化合物区分开来 I类和II类凸轮，我们将通过确定a)来表征我们新凸轮的结构和动力学效应。 它们对乙肝病毒衣壳形态和细胞内定位的影响，b)与乙肝病毒野生型和 已知的突变株Cp，c)对主要的CAM耐药的乙肝病毒株的耐药性和活性，以及d)或 衣壳之间的联系。拟议研究的结果将验证我们新的III类CAM，当 与其他方法相结合将提供临床前的概念验证，以实现新的治疗策略 在减少治疗持续时间和进展为肝细胞癌的同时消除乙肝病毒。