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

描述(申请人提供)：人类疱疹病毒家族包含8个成员，分为三个亚家族，分别命名为阿尔法、贝塔和伽马。阿尔法疱疹病毒包括单纯疱疹病毒1型(HSV-1)、单纯疱疹病毒2型(HSV-2)和水痘带状疱疹病毒(VZV)。贝塔疱疹病毒包括人类巨细胞病毒(HCMV)、人类疱疹病毒6的两个变种(HHV-6A、HHV-6B)和人类疱疹病毒7(HHV-7)。伽马疱疹病毒包括爱泼斯坦-巴尔病毒(EBV)和人类疱疹病毒8(HHV-8)。疱疹病毒感染通常是获得性的，其中许多引起了重大的健康问题，特别是在免疫功能低下的患者群体中(例如，移植接受者、艾滋病患者和老年人)。由于目前治疗方法的范围很窄，出现了耐药病毒株，以及目前治疗方案的毒性有限，因此确实需要有效和安全的新药物来治疗疱疹病毒感染，特别是由免疫受损患者的耐药病毒株引起的感染。我们先前已经确定亚甲基环丙烷核苷(MCPN)是HCMV、HHV-6和HHV-8的有效抑制剂。SBIR第一阶段提案的最初目标是寻找新的MCPN类似物，在保持HCMV活性的同时，具有更强的抗HHV6/8效力和疗效。我们已经超过了SBIR第一阶段的目标，现在已经鉴定出具有非常不寻常的、广泛的抗疱疹活性的新型MCPN类似物，其中包括阿尔法、贝塔和伽马疱疹病毒，包括抗阿昔洛韦的菌株。据我们所知，这种广谱活性在现有的抗疱疹病毒药物中尚未见过。这项SBIR第二阶段建议的主要目标是在动物模型中评估有限数量的在小鼠毒性、PK/PD和有效性(HSV/CMV/VZV)方面最有效的MCPN，以确定最终的广谱抗疱疹病毒临床前候选药物和备用化合物，以推进IND使大鼠GLP毒理学和安全性药理学研究。

DESCRIPTION (provided by applicant): The human herpesviridae family contains eight members divided into three subfamilies, designated alpha, beta and gamma. The alpha herpes viruses include herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2) and varicella zoster virus (VZV). The beta herpes viruses include human cytomegalovirus (HCMV), two variants of human herpes virus 6 (HHV-6A, HHV-6B), and human herpes virus 7 (HHV-7). The gamma herpes viruses include Epstein-Barr virus (EBV) and human herpes virus 8 (HHV-8). Herpes virus infections are commonly acquired, and many present major health concerns, especially among immunocompromised patient populations (e.g., transplant recipients, AIDS patients, and the elderly). Because of the narrow spectrum of current therapeutics, emergence of resistant virus strains, and the limiting toxicities of current treatment options, there is a definite need for new agents that are effective and safe for treating herpes virus infections, particularly those caused by drug-resistant virus strains in the immunocompromised patient. We have previously identified the methylenecyclopropane nucleosides (MCPNs) as potent inhibitors of HCMV, HHV- 6 and HHV-8. The original goal of the SBIR Phase I proposal was to identify new MCPN analogs with even greater anti-HHV6/8 potency and efficacy, while maintaining HCMV activity. We have exceeded that SBIR Phase I goal, and have now identified novel MCPN analogs with a very unusual, broad anti-herpes spectrum of activity that includes the alpha-, beta- and gamma-herpes viruses, including ACV resistant strains. To our knowledge, this broad spectrum activity has not been seen with existing anti-herpes virus agents. The primary objective of this SBIR Phase II proposal is to evaluate a limited number of the most potent MCPNs in murine toxicity, PK/PD, and efficacy (HSV/CMV/VZV) in animal models to identify a final broad- spectrum anti-herpes virus preclinical candidate, and backup compound, to advance into IND enabling rat GLP toxicology and safety pharmacology studies.