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：
8438484
负责人：
Robert Turner Schooley
金额：
$ 49.99万
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 2014-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8438484
关键词：
9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine American Animal Model Antiviral Agents Biological Assay Biological Models Carcinoma Cells Characteristics 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 chronic liver disease drug discovery experience high risk sexual behavior improved in vivo inhibitor/antagonist liver infection member mortality mouse model mutant novel phosphonate transmission process

项目摘要

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.

丙型肝炎病毒 (HCV) 感染了大约 400 万美国人和 1.7 亿人全球基础。尽管过去两年与血液制品相关的传播大幅减少几十年来，特别是在资源丰富的环境中，注射吸毒者之间的传播仍在继续，而且越来越多的证据表明存在高风险性行为的个体之间存在传播。此外，由于该病毒引起的大多数发病与慢性肝病有关，并且需要 20 年或更长时间才能形成，无论如何，预计至少在未来十年美国丙肝相关发病率和死亡率将会上升当前传输速率。过去10年，治疗方法取得了稳步进步随着聚乙二醇化干扰素（PEG-Ifn）-利巴韦林治疗方案的发展，出现了多种选择。尽管有这些进展，只有大约 50% 的具有美国最常见 HCV 基因型（基因型 1）的人可以耐受整个疗程，对基于 PEG-Ifn 的治疗完全有反应。禁忌症和毒性当前治疗方案的组成部分使许多治疗候选者无法开始或完成完整的治疗治疗过程中，并表明以 Ifn 为基础的疗法不太可能取得实质性进一步改善。近3年来，小分子药物的研发取得了越来越大的进展。 HCV NS3/NS4a 蛋白酶和 NS5b 聚合酶抑制剂。针对每个分子的化合物目标已在体内清楚地证明了概念验证，并且与 PEG-Ifn 的组合研究正在进行中。 HCV 与 HIV 有两个共同的关键特性：高复制率和低复制保真度，这使得它高度有效的所有小分子治疗方案可能需要针对多种药物使用多种药物分子靶标。正如本申请中所述，两个研究小组正在合作优化一系列口服药物针对 HCV 聚合酶的活性核苷膦酸酯化合物。我们创造了一系列烷氧基烷基核苷膦酸酯衍生物，可显着增强抗病毒活性和母体核苷的药代动力学特性。使用我们已成功采用的方法针对艾滋病毒、痘病毒和疱疹病毒的药物发现我们建议系统地评估这一点 HCV 感染的方法，认为 HCV 治疗的下一个实质性进展可能需要开发无干扰素治疗方案，并且这将需要大量可用的比目前现有的更多小分子 HCV 抑制剂。