Prodrug Strategies for HCV Nucleoside Lead Development

HCV 核苷先导药物开发的前药策略

• 批准号: 8249663
• 负责人: Katherine L Seley-Radtke
• 金额: $ 19.41万
• 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 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8249663
• 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 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. PUBLIC HEALTH RELEVANCE: More than 200 million people worldwide are estimated to be chronically infected with the hepatitis C virus (HCV) and the only currently available treatment is efficacious in less than half of treated patients, as well as being plagued with treatment-limiting side effects and toxicity. This application focuses on a series of nucleoside analogues that should exhibit potent and synergistic activity against the HCV RNA-dependent RNA polymerase (NS5B due to a number of strategically designed structural features. The impact of this project goes beyond just global health research, but will also provide valuable hands on training for students. Moreover, the information obtained about nucleoside prodrugs and HCV polymerases will be highly applicable across a broad scope of viral diseases.

描述（由申请人提供）：估计全世界有超过2亿人患有HCV长期感染HCV，因此有可能发展危及生命的肝病的风险。目前唯一可用的治疗方法是核苷类似物类似物的干扰素和利巴韦林的联合疗法。不幸的是，这种组合在不到一半的患者中表现出有限的功效，并且受到治疗限制副作用和毒性的困扰。此外，在临床试验中越来越多地报道了对研究性小分子的耐药性的报道，也强调了对新的，更有效的治疗的需求。许多改良的核苷作为HCV聚合酶的抑制剂表现出了有效的活性，但是递送，毒性，不稳定性和/或差的药代动力学的无效问题使许多有希望的类似物变得不合适，因此许多研究人员正在使用“使用前药”或“掩盖”或“掩盖”或“掩盖” “在核苷的5'-OH上组，以克服这些问题。该应用集中在一系列扩展的嘌呤核苷类似物上，我们预计，由于许多策略性设计的结构特征，我们预计将对HCV RNA依赖性RNA聚合酶（RDRP）NS5B表现出有效的活性。该应用程序的影响是两个方面；第一，由于迫切需要更有效的HCV治疗，因此药物发现最终可能会产生全球影响。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的药物输送方法知识的广度。此外，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，但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有关聚合酶获得的信息将在广泛的疾病范围内高度适用。 公共卫生相关性：据估计，全世界有超过2亿人患有丙型肝炎病毒（HCV），目前唯一可用的治疗在不到一半的治疗患者中有效，并且受到治疗限制的一面影响和毒性。该应用的重点是一系列核苷类似物，这些类似物应表现出对HCV RNA依赖性RNA聚合酶的有效和协同活性（由于许多战略性设计的结构特征，NS5B引起的。此外，还为学生提供了宝贵的培训，有关核苷前药和HCV聚合酶的信息将在广泛的病毒疾病范围内高度适用。