Orally Active Nucleoside Phosphonates for Hepatitis C Virus

描述(申请人提供)：丙型肝炎病毒(丙型肝炎病毒)感染约400万美国人和全球1.7亿人。尽管在过去20年中，与血液制品有关的传播大幅减少，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，而且有越来越多的证据表明，在从事更高风险性行为的个人中传播。此外，由于该病毒的大部分发病率与慢性肝病有关，需要20年或更长时间才能发展起来，因此，无论目前的传播率如何，至少在未来十年内，美国与丙型肝炎相关的发病率和死亡率预计都会增加。在过去的10年里，随着聚乙二醇化干扰素(PEG化干扰素)-利巴韦林治疗方案的演变，治疗方案得到了稳步的改进。尽管取得了这些进展，但在美国最常见的丙型肝炎病毒基因(基因1)患者中，只有大约50%的人可以耐受整个疗程，对基于聚乙二醇干扰素的治疗完全有反应。当前方案的禁忌症和毒副作用使许多候选治疗方案无法开始或完成整个疗程的治疗，并表明基于干扰素的治疗不太可能有实质性的进一步改进。在过去的3年里，在开发小分子的丙型肝炎病毒NS3/NS4a蛋白酶和NS5B聚合酶抑制剂方面取得了越来越大的进展。针对每个分子靶点的化合物已经清楚地在体内证明了概念，与聚乙二醇干扰素的联合研究正在进行中。丙型肝炎病毒与艾滋病毒有两个共同的关键特性：高复制率和低复制保真度，这使得有效的所有小分子方案极有可能需要使用针对几个分子靶点的多个药物。正如本申请中所概述的，两个研究小组正在合作优化一系列针对丙型肝炎病毒聚合酶的口服活性核苷膦化合物。我们已经创造了一系列烷氧基烷基核苷膦酸衍生物，大大增强了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HIV、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背景下系统地评估这种方法，认为丙型肝炎病毒治疗的下一个实质性进展可能需要开发无干扰素方案，这将需要比目前可用的更多的小分子丙型肝炎病毒抑制剂。公共卫生相关性：在本申请中，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。我们的方法使用新的脂尾，通过在感染细胞内浓缩分子的活性成分来极大地增强抗病毒活性。如果我们在这些努力中取得成功，我们相信这类分子可以极大地改善丙型肝炎病毒感染者的治疗选择。

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.