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，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 发生肝炎，肝硬化和肝细胞癌（HCC）的风险。当前的抗HBV治疗 期权抑制病毒，但不能消除病毒，需要昂贵的终身治疗。所有FDA都批准了 治疗方法无法靶向共价闭合圆形DNA（CCDNA；与病毒相关的HBV 持久性）或对病毒增殖至关重要的病毒capsid。我们在此应用程序中的方法是 靶标圈组件，这对于复制至关重要，因为CCCDNA的DNA合成仅发生 在衣壳编码的粒子中。 HBV核蛋白（CP）构成病毒式衣壳组件中的亚基， 衣壳组件调节器（CAM）加速了衣壳组件的动力学，从而防止pol- PGRNA复合物封装和阻止HBV复制。凸轮还干扰CCCDNA转录/DE 在感染的早期步骤中的Novo形成。作为我们正在进行的HBV CAM发现计划NIH-的一部分 在过去的四年中，我们得到了支持，我们已经成功地开发了几种高潜力（亚微摩尔） II类CAM与我们的一种铅化合物之一，在2020年10月进入1阶段临床试验。但是， 有许多障碍可能使我们为FDA批准而努力的障碍。在这里，我们第一次描述 新型的同性恋或异二聚体凸轮，在皮莫尔范围内培养中表现出选择性抗HBV活性。 因为链接两个凸轮部分的二聚体结构可以与一个capsid或一个不同的位点相互作用或 甚至将两个（或更多）的衣壳连接在一起，我们假设这些化合物将具有更多 对HBV衣壳组件的深刻影响比已知的I类或II级凸轮。基于效力和独特 作用方式（MOA）我们将新化合物称为“ III类”凸轮。我们建议评估这些班级 III凸轮通过追求三个特定目标：1）化学优化和表征独特的CAM 由新单体制成的同性恋/异二聚体； 2）表征（结构，生化和生物学上） 新型CAM Homo/异二聚体结合与HBV Capsid的相互作用； 3）确定药代动力学（PK）和 新型CAM HOMO和异二聚体的体内效率。新颖的同性恋和异二聚体将被合成，并且 评估以达到最大的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 I级和II凸轮，我们将通过确定a来表征我们的新凸轮的结构和动态效应 它们对HBV衣壳形态及其在细胞中的定位的影响，b）与HBV野生型的结合和 已知的突变体CP，c）耐药性和对主要抗CAM耐药性HBV菌株的活性以及d）内部或内部或 界限间连接。拟议研究的结果将验证我们的新型III类CAM，当时 结合其他方式将为临时概念证明，以实现新的疗法策略 消除HBV，同时减少治疗持续时间并发展为HCC。