Mechanistic Approaches to Inhibition of Emerging DNA Viruses

项目总结 美国国立卫生研究院已确认一组传染性病毒“正在出现”，因为它们对公众的威胁越来越大 健康。这份高优先级列表包括几种DNA病毒。感染DNA病毒会导致显著的 疾病，但很少有药物被批准用于治疗这类病原体。西多福韦(CDV，HPMPC)是一种非环类药物 核苷磷酸盐(ANP)，已知对一系列DNA病毒具有活性。然而，像其他人一样 ANPS作为一类，CDV有明显的缺点，包括先天缺乏口服生物利用度，相对较低 效力和肾毒性。CDV及其腺嘌呤类似物HPMPA的某些新型N-烷基酪氨酰胺前药 最近由南加州大学的查尔斯·麦肯纳教授设计和合成的PI 与亲本相比，(USC)在体外对CMV和其他几种DNA病毒的效力大大增强 药物和改进的选择性指数。一种重要的病毒依赖的效力、选择性和有效性的变异 观察到了增强，这还没有从机制上解释。在这个R21项目中，这些前药 以及一系列具有修饰的促进结构的类似物，旨在影响磷脂酶C的激活 被评估在生理条件下的稳定性和渗透性以及对CMV，HSV1， VACV和两种新出现的DNA病毒：HHV-6B和BK病毒。这项研究将重点放在关联个体上 被感染细胞摄取和药物释放到细胞质中摄取的启动子结构特征 利用新的5-BrHPMPU前药衍生物作为探针，为每种病毒插入病毒DNA。这些信息相互关联 具有稳定性、新陈代谢和体外抗病毒效力的数据将为这五种病毒提供重要的见解 关于这类新的前体药物特殊但不同效力的潜在机制 被调查的病毒，同时引入了一种创新的分子工具来确定药物的促进性 有效性。它还有望识别新的、高度有效的化合物，以便未来开发成有效的 这些病毒感染的治疗方法。

PROJECT SUMMARY The NIH has identified a group of infective viruses as “emerging” because they are a growing threat to public health. This high priority list includes several DNA viruses. Infections with DNA viruses result in significant disease, but few drugs have been approved for this class of pathogens. Cidofovir (CDV, HPMPC) is an acyclic nucleoside phosphonate (ANP) known to exhibit activity against a spectrum of DNA viruses. However, like other ANPs as a class, CDV has significant drawbacks, including inherent lack of oral bioavailability, relatively low potency and nephrotoxicity. Certain novel N-alkyl tyrosinamide prodrugs of CDV and its adenine analog HPMPA recently designed and synthesized by the PI, Professor Charles McKenna at the University of Southern California (USC) exhibit greatly enhanced in vitro potency against CMV and several other DNA viruses relative to the parent drugs and improved selectivity indices. An important virus-dependent variation in potency, selectivity and efficacy enhancement is observed, which has not been explained mechanistically. In this R21 project, these prodrugs and a series of analogs with modified promoiety structures designed to affect activation by phospholipase C will be evaluated for stability and permeability under physiological conditions and for activity against CMV, HSV1, VACV and two emerging DNA viruses: HHV-6B and BK virus. The research will focus on associating individual promoiety structural features with uptake into infected cells and release of drug into the cytoplasm for uptake into viral DNA for each virus, using novel 5-BrHPMPU prodrug derivatives as probes. This information, correlated with the stability, metabolism and in vitro antiviral efficacy data for the five viruses will provide important insights into the mechanism underlying the exceptional but varied potency of this new class of prodrugs with respect to the viruses investigated, while introducing an innovative molecular tool to determine drug promoiety effectiveness. It is also expected to identify new, highly potent compounds for future development into effective therapies for infections by these viruses.