Development of Novel Hepatits C Virus Inhibitors

新型丙型肝炎病毒抑制剂的开发

• 批准号: 7671188
• 负责人: TODD Bernard PARSLEY
• 金额: $ 14.14万
• 依托单位: IMQUEST BIOSCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-06 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7671188
• 关键词: Antiviral Agents; Applications Grants; Biochemical; Biological Assay; Bovine Viral Diarrhea Viruses; Cell Line; Cells; Complex; Data; Development; Drug Design; Drug Kinetics; Drug resistance; Engineering; Evaluation; Funding Mechanisms; Gene Expression; Generations; Genes; Genetic Determinism; Goals; Grant; Hepatitis C; Hepatitis C virus; In Vitro; Individual; Informatics; Interferons; Label; Lead; MDCK cell; Mediating; Metabolic Pathway; Molecular Genetics; Molecular Target; Mutation; Neomycin resistance gene; Pattern; Pharmaceutical Preparations; Pharmacology and Toxicology; Pharmacotherapy; Phase; Poison; Population; Property; Protocols documentation; RNA replication; Relative (related person); Replicon; Reporting; Research; Resistance; Resistance profile; Ribavirin; Role; Safety; Selection Criteria; Serial Passage; Series; Signal Transduction; Small Business Innovation Research Grant; Structure-Activity Relationship; System; Testing; Therapeutic; Therapeutic Index; Toxic effect; Toxicity Tests; Toxicology; Viral; Virus Inhibitors; Virus Replication; Work; analog; anti-hepatitis C; antibiotic G 418; base; cellular targeting; commercialization; design; drug development; established cell line; improved; in vitro Assay; in vivo; inhibitor/antagonist; insight; meetings; novel; progesterone 11-hemisuccinate-(2-iodohistamine); public health relevance; research study; small molecule; therapeutic development; uptake; viral RNA; virus host interaction

DESCRIPTION (provided by applicant): The goals this Phase I SBIR grant are focused on the development of PG 301029 and chemically related compounds as therapeutics for treatment of hepatitis C virus infection. PG 301029 is a small molecule inhibitor of hepatitis C virus (HCV) replication that has been shown to be less toxic and have a larger therapeutic index than the approved therapeutic ribavirin in in vitro assays using the HCV surrogate bovine viral diarrhea virus (BVDV). The relative decrease in toxicity of PG 301029 compared to that of ribavirn was also observed when studies were extended to include a panel of primary and established cell lines, suggesting the potential of PG 301029 as a safer and more efficacious drug than ribavirin for the treatment of HCV. Additionally, preliminary in vivo toxicology studies indicate that the compound is well tolerated and has a pharmacokinetic profile appropriate for drug development. We will perform a structure activity relationship (SAR) based examination of an additional fifteen compounds previously identified as inhibitors of BVDV replication in a screen of 155 near neighbor related compounds for their ability to inhibit replication of an HCV replicon. These studies will provide insight into the functional structural features of PG 301029 which contribute to the antiviral activity and will be the basis for chemi- informatic studies to develop second generation PG 301029 based inhibitors as a component of the Phase II SBIR proposal. PUBLIC HEALTH RELEVANCE: The goal of this Phase I SBIR is to identify and characterize novel inhibitors of hepatitis C virus replication. The lead compound for development, PG 301029, is a small molecule that acts through a novel mechanism of action to reduce viral RNA accumulation in BVDV-infected and HCV replicon and has a therapeutic index greater > 500 against BVDV. Structure activity relationship (SAR) analysis with 15 chemically related molecules that have shown antiviral activity against BVDV will be performed using a HCV replicon cell line to define the structural features of PG 301029 which contribute to their functional antiviral activity . The collective data will be the basis for chemi-informatic studies to develop second generation inhibitors as a component of the Phase II SBIR proposal. We will also use hypothesis directed research to define the mechanism of action of the antiviral activity by examining alterations in macromolecular interactions and gene expression in PG 301029 treated cells.

描述（由申请人提供）：该阶段I SBIR赠款的目标侧重于PG 301029和化学相关的化合物作为治疗丙型肝炎病毒感染的治疗剂。 PG 301029是一种小分子丙型肝炎病毒（HCV）复制的抑制剂，与使用HCV替代性替代性替代性的替代性替代性的替代性的治疗方法相比，它被证明毒性较小，具有更大的治疗指数。当研究扩展到包括一系列原发性和已建立的细胞系时，还观察到了PG 301029的毒性相对降低，而与ibavirn相比，PG 301029的潜力比Riabavirin对HCV的处理，这表明PG 301029的潜力更安全，更有效。此外，初步体内毒理学研究表明，该化合物的耐受性很好，并且具有适合药物开发的药代动力学特征。我们将对先前鉴定为BVDV复制抑制剂的另外15种相关化合物的抑制剂进行基于结构活动关系（SAR）的研究（SAR）检查，以抑制HCV复制子的复制能力。这些研究将洞悉PG 301029的功能结构特征，这些特征有助于抗病毒活性，并将成为化学信息研究的基础，以开发基于第二PG 301029的抑制剂作为II期SBIR提案的组成部分。公共卫生相关性：I阶段SBIR的目标是识别和表征新型丙型肝炎病毒复制的抑制剂。发育的铅化合物PG 301029是一个小分子，它通过一种新型的作用机理起作用，以减少受BVDV感染的病毒RNA积累和HCV复制子的积累，并且具有针对BVDV的治疗指数> 500。将使用HCV复制子细胞系进行抗病毒活性的15个化学相关分子的结构活性关系（SAR）分析，以定义PG 301029的结构特征，从而有助于其功能性抗病毒活性。集体数据将是化学研究的基础，以开发第二代抑制剂作为II期SBIR提案的组成部分。我们还将使用假设的指示研究来通过检查大分子相互作用的改变和PG 301029处理过的细胞中的基因表达来定义抗病毒活性的作用机理。