HBV Capsid Effectors

HBV衣壳效应器

• 批准号: 9368272
• 负责人: Raymond Felix Schinazi
• 金额: $ 56.3万
• 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 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9368272
• 关键词: Adverse effects; Antigens; Antiviral Agents; Area; Benchmarking; Binding; Bioavailable; Biochemical; Biological; Biological Availability; Capsid; Cells; Chemicals; Chronic; Chronic Hepatitis B; Circular DNA; Cirrhosis; Core Protein; Crystallography; DNA biosynthesis; Data; Development; Drug Kinetics; Drug Targeting; Electron Microscopy; HIV; HIV/HCV; Hepatitis; Hepatitis B; Hepatocyte; Human; Individual; Interferons; Lead; Liver; Modality; Modeling; Monitor; Mus; Nucleosides; Oral; Persons; Pharmaceutical Preparations; Population; Primary carcinoma of the liver cells; Public Health; Quality of life; Regimen; Resistance; Resistance profile; Selection Criteria; Series; Serotyping; Serum; System; Testing; Therapeutic; Toxic effect; Vaccines; Viral; Viral reservoir; Virus; Virus Diseases; Virus Replication; analog; anti-hepatitis B; co-infection; cytotoxicity; design; epidemiologic data; follow-up; glyoxamide; high risk; improved; in vivo; innovation; interdisciplinary approach; life time cost; liver function; macrophage; mortality; mouse model; novel; novel drug class; novel therapeutic intervention; novel therapeutics; nucleoside analog; particle; pre-clinical; prevent; small molecule; treatment duration

PROJECT SUMMARY / ABSTRACT Hepatitis B virus (HBV) remains a major worldwide public health challenge with 10-20 million chronically infected individuals developing cirrhosis, characterized by a decline and loss of liver function with a significantly decreased quality of life and a high mortality rate. While current therapies effectively control the virus with few side effects, they do not cure since none target the HBV covalently closed- circular DNA (cccDNA; associated with viral persistence). Our innovative approach targets capsid assembly which is essential for replication, as DNA synthesis from cccDNA occurs exclusively within the capsid encoded particle. Therefore, the focus of this proposal is on developing small molecules targeting disruption of capsid formation which could ultimately impact cccDNA stability and/or formation and also reduce duration of treatment in HBV infected persons. We are developing a novel class of Capsid Assembly Effectors (CAE) that target capsid formation (glyoxamide derivatives). Recently, we have identified a highly potent “lead” compound IV with selective activity at 3 nM. The proposed specific AIMS will systematically define the pre-clinical parameters (including activity, toxicity, stability, oral bioavailability, capsid binding interaction) of this novel class of CAE: AIM 1: to chemically optimize and characterize a unique series of glyoxamide CAE, including our “lead” compound IV; AIM 2: to structurally, biochemically, and biologically characterize novel CAE binding interaction with HBV capsid.; and AIM 3: to determine pharmacokinetics (PK) and efficacy of novel CAE and combination regimens in two different mouse models for HBV infection. Results from these studies will validate our novel class of small molecule CAE, which when combined with other modalities (e.g., nucleoside analogs) could provide preclinical “proof of concept” towards a novel therapeutic strategy with reduced treatment duration and a functional cure for HBV infection.

项目摘要 /摘要 丙型肝炎病毒（HBV）仍然是全球范围内的主要公共卫生挑战 长期感染的个体发展出肝硬化，其特征是肝功能的下降和丧失 具有显着改善的生活质量和高死亡率。而当前的治疗有效 控制病毒几乎没有副作用，它们无法治愈，因为没有一个针对HBV共价闭合 - 圆形DNA（CCDNA；与病毒持久性相关）。我们的创新方法针对Capsid 组装对于复制至关重要，因为CCCDNA的DNA合成仅发生在 衣壳编码的粒子。因此，该提议的重点是开发小分子 靶向上皮形成的破坏，最终可能影响CCCDNA稳定性和/或形成 还减少了HBV感染者的治疗持续时间。我们正在开发一个新颖的课程 靶标成形胶囊形成（乙二胺衍生物）的衣壳组件效应子（CAE）。最近，我们 已经确定了在3 nm处具有选择性活性的高潜力“铅”化合物IV。提议 具体目标将系统地定义临床前参数（包括活动，毒性，稳定性， 这种新型CAE类的口服生物利用度，衣壳结合相互作用）：目标1：化学优化 并描述了一系列独特的乙二胺CAE，包括我们的“铅”化合物IV；目标2：到 在结构上，生化和生物学上表征与HBV的新型CAE结合相互作用 CAPSID。和目标3：确定新型CAE和组合的药代动力学（PK）和效率 HBV感染的两种不同小鼠模型中的方案。这些研究的结果将证明我们 新型的小分子CAE，当与其他模态结合时（例如核苷 类似物）可以为新型的热策略提供临床前的“概念证明”，并减少 治疗持续时间和HBV感染的功能治疗。