Orally Active Nucleoside Phosphonates for Hepatitis C Virus

口服活性核苷磷酸盐治疗丙型肝炎病毒

基本信息

批准号：
8121804
负责人：
Robert Turner Schooley
金额：
$ 3.89万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8121804
关键词：
American Animal Model Antiviral Agents Biological Assay Biological Models Carcinoma Cells Characteristics Chronic Clinical Data Development Drug Kinetics Drug resistance Evaluation Evolution Exhibits Genotype HIV Hand Hepatic Hepatitis B Hepatitis C Hepatitis C virus Herpesviridae In Vitro Individual Infection Injecting drug user Interferons Lead Lipids Liver Liver diseases Luciferases Molecular Molecular Target Morbidity - disease rate Mus Nucleosides Oral Parents Peptide Hydrolases Polymerase Poxviridae Preparation Process Property Regimen Replicon Research Resistance Ribavirin Series System Tail Therapeutic Tissues Toxic effect Toxicology Transgenic Mice Treatment Protocols Virus Virus Diseases Virus Inhibitors Virus Replication Work adefovir dipivoxil analog anti-hepatitis C base blood product chemotherapy drug discovery experience high risk sexual behavior improved in vivo inhibitor/antagonist liver infection member mortality mouse model mutant novel phosphonate public health relevance transmission process

项目摘要

DESCRIPTION (provided by applicant): Hepatitis C Virus (HCV) infects approximately 4 million Americans and 170 million people on a worldwide basis. Despite substantial reductions in blood product-related transmission over the past two decades, especially in resourced settings, transmission among injecting drug users continues and there is increasing evidence of transmission among individuals engaged in higher risk sexual behaviors. Furthermore, since most morbidity from the virus is related to chronic liver disease and requires 20 or more years to develop, HCV-related morbidity and mortality is projected to increase in the US for at least the next decade regardless of the current transmission rate. Over the last 10 years there have been steady improvements in therapeutic options with the evolution of pegylated interferon (PEG-Ifn)-ribavirin based treatment regimens. Despite these advances, only about 50% of those with the HCV genotype most common in the US (Genotype 1) who can tolerate a full course of therapy respond fully to PEG-Ifn based therapy. Contraindications and toxicities to components of the current regimen preclude many treatment candidates from initiating or completing a full course of therapy and suggest that substantial further improvement in Ifn-based therapies is unlikely. Over the past 3 years there has been increasing progress in the development of small molecular inhibitors of the HCV NS3/NS4a protease and the NS5b polymerase. Compounds directed at each molecular target have clearly demonstrated proof-of-concept in vivo and combination studies with PEG-Ifn are underway. HCV shares two critical properties with HIV: high replication rates and low replicative fidelity, that make it highly likely that efficacious all small molecular regimens will require the use of multiple agents directed at several molecular targets. As is outlined in this application, two research groups are collaborating to optimize a series of orally active nucleoside phosphonate compounds directed at the HCV polymerase. We have created a series of alkoxyalkyl nucleoside phosphonate derivatives that substantially enhance both the antiviral activity and the pharmacokinetic properties of parent nucleosides. Using an approach that we have successfully employed in drug discovery directed at HIV, poxviruses and herpes viruses we propose to systematically evaluate this approach in the setting of HCV infection with the view that the next substantial advance in HCV therapeutics will likely require the development of interferon-free regimens and that this will require the availability of a much larger array of small molecular HCV inhibitors than is currently in hand. PUBLIC HEALTH RELEVANCE: In this application we propose to construct new compounds that are active against hepatitis C virus, a major cause of liver disease and hepatic cellular carcinoma. Our approach uses novel lipid tails that greatly enhance antiviral activity by concentrating the active component of the molecule within infected cells. If we are successful in these efforts, we believe this class of molecules could greatly improve treatment options for people with HCV infection.

描述（由申请人提供）：丙型肝炎病毒 (HCV) 感染约 400 万美国人和全球 1.7 亿人。尽管在过去二十年中，与血液制品相关的传播大幅减少，特别是在资源丰富的环境中，但注射吸毒者之间的传播仍在继续，并且越来越多的证据表明从事高风险性行为的个人之间存在传播。此外，由于该病毒的大多数发病率与慢性肝病有关，并且需要 20 年或更长的时间才能发展，因此无论目前的传播率如何，预计至少在未来十年美国与 HCV 相关的发病率和死亡率都会增加。在过去的 10 年里，随着基于聚乙二醇化干扰素 (PEG-Ifn)-利巴韦林的治疗方案的发展，治疗选择不断改进。尽管取得了这些进展，但在美国最常见的 HCV 基因型（基因型 1）患者中，只有约 50% 能够耐受整个疗程的患者对基于 PEG-Ifn 的治疗完全有反应。目前治疗方案的禁忌症和毒性使许多候选治疗方案无法开始或完成整个疗程，这表明基于 Ifn 的治疗不太可能取得实质性进一步改善。过去 3 年里，HCV NS3/NS4a 蛋白酶和 NS5b 聚合酶小分子抑制剂的开发取得了越来越大的进展。针对每个分子靶标的化合物已在体内得到了明确的概念验证，并且与 PEG-Ifn 的组合研究正在进行中。 HCV 与 HIV 共有两个关键特性：高复制率和低复制保真度，这使得有效的所有小分子治疗方案很可能需要使用针对多个分子靶点的多种药物。正如本申请所述，两个研究小组正在合作优化一系列针对 HCV 聚合酶的口服活性核苷膦酸酯化合物。我们创建了一系列烷氧基烷基核苷膦酸酯衍生物，可显着增强母体核苷的抗病毒活性和药代动力学特性。使用我们在针对艾滋病毒、痘病毒和疱疹病毒的药物发现中成功采用的方法，我们建议在丙型肝炎病毒感染的情况下系统地评估这种方法，认为丙型肝炎治疗的下一个实质性进展可能需要干扰素的开发-免费治疗方案，这将需要比目前现有的更多的小分子 HCV 抑制剂。公共健康相关性：在此应用中，我们建议构建对丙型肝炎病毒具有活性的新化合物，丙型肝炎病毒是肝病和肝细胞癌的主要原因。我们的方法使用新型脂质尾部，通过将分子的活性成分集中在受感染的细胞内，大大增强抗病毒活性。如果我们的这些努力取得成功，我们相信这类分子可以极大地改善 HCV 感染者的治疗选择。