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.

项目总结/摘要 B型肝炎病毒（HBV）仍然是全球主要的公共卫生挑战， 慢性感染个体发展为肝硬化，以肝功能下降和丧失为特征 生活质量显著下降，死亡率很高。虽然目前的疗法有效地 控制病毒，副作用少，他们不治愈，因为没有目标的HBV共价关闭- 环状DNA（cccDNA;与病毒持久性相关）。我们的创新方法针对衣壳蛋白 这是复制所必需的，因为cccDNA的DNA合成仅发生在 衣壳编码颗粒。因此，这项提案的重点是开发小分子 靶向破坏衣壳形成，这可能最终影响cccDNA稳定性和/或形成 并且还减少HBV感染者的治疗持续时间。我们正在开发一类新颖的 靶向衣壳形成的衣壳组装效应子（CAE）（乙二醛酰胺衍生物）。最近我们 已经鉴定出在3 nM下具有选择活性的高度有效的“先导”化合物IV。拟议 具体的AIMS将系统地定义临床前参数（包括活性、毒性、稳定性， 口服生物利用度，衣壳结合相互作用），这类新的CAE：目的1：化学优化 并表征了一系列独特的乙二醛酰胺CAE，包括我们的“铅”化合物IV; AIM 2： 在结构上、生化上和生物学上表征与HBV新型CAE结合相互作用 衣壳。和AIM 3：确定新型CAE和组合的药代动力学（PK）和疗效 在两种不同的HBV感染小鼠模型中，这些研究的结果将验证我们的 新型的小分子CAE，当与其他形式（例如，核苷 类似物）可以提供临床前“概念验证”，以实现具有降低的 治疗持续时间和HBV感染的功能性治愈。