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

• 批准号: 7655603
• 负责人: Robert Turner Schooley
• 金额: $ 57.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 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/7655603
• 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; 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

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）在全球范围内感染了约400万美国人和1.7亿人。尽管在过去的二十年中，与血液产品相关的传播大幅减少，尤其是在资源丰富的环境中，但注射吸毒者的传播仍在继续，并且越来越多的证据表明，从事较高风险性行为行为的个人之间的传播。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年或更长时间才能发育，因此与HCV相关的发病率和死亡率预计在美国至少在接下来的十年中会增加，而与当前的传输率无关。在过去的十年中，随着基于PEGYPER干扰素（PEG-IFN）基于Ribavirin的治疗方案的进化，治疗选择的稳定改善。尽管取得了这些进步，但在美国最常见的HCV基因型的人中，只有大约50％的人可以忍受完整的治疗方法对基于PEG-IFN的治疗做出完全反应。对当前方案的组成部分的禁忌症和毒性阻止了许多候选者启动或完成完整的治疗方法，并暗示不太可能进一步改善基于IFN的疗法。在过去的三年中，HCV NS3/NS4A蛋白酶和NS5B聚合酶的小分子抑制剂的发展进展不断增加。针对每个分子靶标的化合物清楚地表明了体内概念验证，并且正在与PEG-IFN进行组合研究。 HCV与HIV共享两种关键特性：高复制率和低复制性忠诚度，这使得所有小分子方案的有效性都可能需要使用针对多个分子靶标的多种药物。如本应用程序中概述的那样，两个研究组正在协作，以优化一系列针对HCV聚合酶的口服活性核苷化合物。我们创建了一系列烷基烷基核苷磷酸衍生物，这些衍生物显着增强了父核苷的抗病毒活性和药代动力学特性。使用我们在针对HIV的药物发现中成功采用的一种方法，我们建议在HCV感染中系统地评估这种方法，认为HCV疗法的下一个实质性进步可能需要无用的疗法的开发，而这将需要与当前更大的小型hC的可用性相比，这可能需要无效的途径。公共卫生相关性：在此应用中，我们建议构建针对乙型肝炎病毒的新化合物，乙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的脂质尾巴，通过将分子的活性成分集中在感染细胞中，从而大大增强了抗病毒活性。如果我们在这些努力方面取得了成功，我们相信这类分子可以大大改善HCV感染患者的治疗选择。