Novel Methylenecyclopropane Analogues as Anti-Human Herpesvirus 6 and 8 Agents

描述（由申请人提供）：对治疗乙型疱疹病毒和伽玛疱疹病毒相关新发感染的有效和安全的新药有很高的需求。一种新的嘌呤核苷类似物，亚甲基环丙烷（MP），已被证明是有希望的抗病毒药物，具有非常不寻常的活性谱，包括β和γ疱疹病毒，这在现有的抗疱疹药物中还没有发现。第一代MP化合物是无环鸟苷的生物立体类似物，其C-O-C部分被亚甲基环丙烷部分取代。第二代MP类似物2,2-双羟基甲基系列对HCMV表现出非常好的活性。在这两种情况下，都产生了Z-异构体和e -异构体，其中Z异构体表现出最好的综合效力。有限数量的第一代和第二代MP的类似物显示出迄今为止发现的对HHV-6和HHV-8复制的一些最有效的抑制作用。该提议的假设是，MP化合物的广泛化学修饰将识别出具有更强效力和功效的新分子，特别是针对HHV-6和HHV-8。已证实的药物化学构效关系（SAR）方法将用于提高MP化合物系列对HHV-6和HHV-8的效力。本提案的总体目标是开发针对新发感染性疾病HHV-6和HHV-8的新疗法。本研究的具体目的是对MP系列化合物进行化学优化，以提高对HHV-6和HHV-8的效力。铅MP化合物也应保持抗HCMV的活性，也可用于治疗这些感染。目前还没有很好的抗病毒药物具有这种独特的特性。该提案的主要里程碑是鉴定出具有优异的HHV-6和HHV-8抑制活性(<1？m)，在原代HEL299细胞中具有最小的细胞毒性（> - 100 μ m）。这些研究中产生的数据将进一步证明其在动物研究中的未来评估（SBIR II期），这将用于确定临床候选药物并支持随后的I/II期HHV-6/-8人类临床研究申请。公共卫生相关性：该提案的假设是，MP化合物的广泛化学修饰将识别出具有更强效力和功效的新分子，特别是针对HHV-6和HHV-8。已证实的药物化学构效关系（SAR）方法将用于提高MP化合物系列对HHV-6和HHV-8的效力。本提案的总体目标是开发针对新发感染性疾病HHV-6和HHV-8的新疗法。

DESCRIPTION (provided by applicant): There is a high need for new agents that are effective and safe for treating betaherpesvirus and gammaherpesvirus related emerging infections. A new series of purine nucleoside analogs, the methylenecyclopropanes (MP), have been shown to be promising antiviral agents with a very unusual spectrum of activity which includes the beta- and gammaherpeviruses, which has not been seen with existing anti-herpes agents. The first generation of MP compounds were biosteric analogs of acyclovir with the C-O-C moiety replaced by the methylenecyclopropane moiety. A second generation of MP analogues, the 2,2-bis-hydroxymethyl series, exhibited very good activity against HCMV. In both cases, the Z- and E-isomers were generated, with the Z isomers demonstrating the best overall potency. A limited number of analogues of both the first and second generation of MP's have exhibited some of the most potent inhibition of HHV-6 and HHV-8 replication so far identified. The hypothesis of this proposal is that extensive chemical modification of the MP compounds will identify new molecules with even greater potency and efficacy specifically against HHV-6 and HHV-8. Proven medicinal chemistry structure activity relationship (SAR) approaches will be used to improve the potency of the MP compound series against HHV-6 and HHV-8. The overall goal of this proposal is to develop novel therapies for the emerging infectious diseases HHV-6 and HHV-8. The specific objective of this proposal is to chemically optimize the MP series of compounds to improve the potency against HHV-6 and HHV-8. Lead MP compounds should also maintain activity against HCMV and would also be useful for treating these infections as well. There is no good antiviral drug with this unique profile. The major milestone of this proposal is to identify lead compounds (3-5) with excellent HHV-6 and HHV-8 inhibitory activity (<1?m) with minimum cytotoxicity in primary HEL299 cells (>100?m). Data generated in these studies will further justify their future evaluation in animal studies (SBIR Phase II), which will be used to identify a clinical candidate and support a subsequent application for Phase I/II HHV-6/-8 human clinical studies. This proposal has the following specific aims and milestones: PUBLIC HEALTH RELEVANCE: The hypothesis of this proposal is that extensive chemical modification of the MP compounds will identify new molecules with even greater potency and efficacy specifically against HHV-6 and HHV-8. Proven medicinal chemistry structure activity relationship (SAR) approaches will be used to improve the potency of the MP compound series against HHV-6 and HHV-8. The overall goal of this proposal is to develop novel therapies for the emerging infectious diseases HHV-6 and HHV-8.