Orally Active Nucleoside Phosphonates for Hepatitis C Virus

描述（由申请人提供）：丙型肝炎病毒（HCV）感染了大约400万美国人和全球1.7亿人。尽管在过去二十年中，特别是在资源丰富的环境中，与血液制品有关的传播大幅减少，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，在从事高风险性行为的个人之间传播。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展，因此无论目前的传播率如何，预计在美国，hcv相关的发病率和死亡率至少在未来十年内都会增加。在过去的10年里，随着聚乙二醇化干扰素(PEG-Ifn)-利巴韦林治疗方案的发展，治疗选择稳步改善。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%的人能够耐受整个疗程的治疗，对PEG-Ifn为基础的治疗有充分的反应。当前方案的禁忌症和成分的毒性使许多候选治疗无法开始或完成整个疗程的治疗，并表明基于ifn的治疗不太可能有实质性的进一步改善。在过去的3年中，HCV NS3/NS4a蛋白酶和NS5b聚合酶的小分子抑制剂的开发取得了越来越大的进展。针对每个分子靶点的化合物已经在体内清楚地证明了概念，与PEG-Ifn的联合研究正在进行中。丙型肝炎病毒与艾滋病毒具有两个关键特性：高复制率和低复制保真度，这使得所有有效的小分子方案都极有可能需要使用针对几个分子靶点的多种药物。正如本申请中概述的那样，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膦酸核苷化合物。我们已经创造了一系列的烷氧烷基核苷膦酸衍生物，大大提高了双亲核苷的抗病毒活性和药代动力学性质。利用我们在针对HIV、痘病毒和疱疹病毒的药物发现中成功使用的方法，我们建议在HCV感染的情况下系统地评估这种方法，并认为HCV治疗的下一个实质性进展可能需要开发无干扰素方案，这将需要比目前更多的小分子HCV抑制剂。公共卫生相关性：在此应用中，我们建议构建新的化合物，对丙型肝炎病毒有活性，丙型肝炎病毒是肝脏疾病和肝细胞癌的主要原因。我们的方法使用新型脂质尾部，通过在感染细胞内浓缩分子的活性成分，大大增强抗病毒活性。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.