Prodrug Strategies for HCV Nucleoside Lead Development

HCV 核苷先导药物开发的前药策略

• 批准号: 8415492
• 负责人: Katherine L Seley-Radtke
• 金额: $ 20.58万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE COUNTY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8415492
• 关键词: Adverse effects; Antiviral Agents; Biological Assay; Cell Culture Techniques; Clinical Trials; Combined Modality Therapy; Development; Diphosphates; Disease; Drug Delivery Systems; Drug Kinetics; Drug Targeting; Drug resistance; Exhibits; Genotype; Guanosine; Hand; Hepatitis C virus; Hepatocyte; Industry; Interferons; Knowledge; Laboratories; Lead; Life; Liver; Liver diseases; Masks; Metabolism; Methodology; Methods; Moderate Exercise; Modification; Mono-S; Nucleosides; Nucleotides; Parents; Patients; Plague; Plasma; Polymerase; Prodrugs; Purine Nucleosides; RNA-Directed RNA Polymerase; Radiolabeled; Relative (related person); Replicon; Reporting; Research; Research Personnel; Ribavirin; Risk; Series; Structure; Students; Techniques; Therapeutic; Thiophenes; Time; Toxic effect; Training; Virus Diseases; Work; analog; anti-hepatitis C; cytotoxicity; design; effective therapy; global health; improved; in vivo; inhibitor/antagonist; nucleoside analog; phosphoramidite; radiotracer; small molecule; stem; tripolyphosphate; uptake; viral RNA

DESCRIPTION (provided by applicant): More than 200 million people worldwide are estimated to be chronically infected with HCV and as a result, at risk for developing life-threatening liver diseases. The only treatment currently available is a combination therapy of pegylated interferon and Ribavirin, a nucleoside analogue. Unfortunately this combination has exhibited limited efficacy in less than half of treated patients, as well as being plagued with treatment- limiting side effects and toxicity. In addition, increasing reports of drug resistance to investigational small molecules in clinical trials are emerging, underscoring the need for new and more effective treatments. A number of modified nucleosides have exhibited potent activity as inhibitors of HCV polymerase, however problems with ineffective delivery, toxicity, instability and/or poor pharmacokinetics have rendered many promising analogues unsuitable, thus many researchers are turning to use of a prodrug, or "masking" group, on the 5'-OH of the nucleoside, to overcome these problems. This application focuses on a series of expanded purine nucleoside analogues that we anticipate will exhibit potent activity against the HCV RNA-dependent RNA polymerase (RdRp) NS5B due to a number of strategically designed structural features. The impact of this application is two-fold; one, the medicinal discoveries could ultimately have a global impact, as more effective HCV treatments are desperately needed. In addition, the basic scientific impacts include expanding the breadth of our knowledge of drug delivery methods for specific targeting of the HCV NS5B polymerase, as well as liver cells. In addition, new and improved methodology for nucleoside analogue synthesis will be investigated. As such, the scientific impact of this work goes beyond just global health research, but will also provide valuable training for students, as the synthetic organic and drug delivery methodologies and the information obtained about polymerases will be highly applicable across a broad scope of diseases.

描述（由申请人提供）：估计全世界有超过 2 亿人慢性感染 HCV，因此面临患上危及生命的肝病的风险。目前唯一可用的治疗方法是聚乙二醇干扰素和核苷类似物利巴韦林的联合疗法。不幸的是，这种组合在不到一半的治疗患者中表现出有限的疗效，并且受到限制治疗的副作用和毒性的困扰。此外，越来越多的临床试验中对研究性小分子产生耐药性的报告不断出现，这凸显了对新的、更有效的治疗方法的需求。许多修饰核苷已表现出作为 HCV 聚合酶抑制剂的有效活性，但无效递送、毒性、不稳定性和/或药代动力学较差的问题使得许多有前途的类似物不适合，因此许多研究人员转向使用前药或“掩蔽” ”小组在核苷的5'-OH上克服了这些问题。该应用重点关注一系列扩展的嘌呤核苷类似物，由于其具有许多策略性设计的结构特征，我们预计这些类似物将表现出针对 HCV RNA 依赖性 RNA 聚合酶 (RdRp) NS5B 的有效活性。该应用程序的影响有两个方面：第一，这些医学发现最终可能会产生全球影响，因为迫切需要更有效的丙肝治疗方法。此外，基本的科学影响包括扩大我们对 HCV NS5B 聚合酶和肝细胞特异性靶向药物输送方法的了解。此外，还将研究新的和改进的核苷类似物合成方法。因此，这项工作的科学影响不仅限于全球健康研究，还将为学生提供宝贵的培训，因为合成有机和药物输送方法以及获得的有关聚合酶的信息将高度适用于广泛的疾病。