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

描述（由申请人提供）：人类疱疹病毒科包含8个成员，分为3个亚科，命名为α、β和γ。α疱疹病毒包括1型单纯疱疹病毒（HSV-1）、2型单纯疱疹病毒（HSV-2）和水痘带状疱疹病毒（VZV）。β疱疹病毒包括人巨细胞病毒（HCMV）、人疱疹病毒6的两种变体（HHV-6A、HHV-6 B）和人疱疹病毒7（HHV-7）。γ疱疹病毒包括EB病毒（EBV）和人疱疹病毒8（HHV-8）。疱疹病毒感染通常是获得性的，并且许多存在主要的健康问题，特别是在免疫功能低下的患者群体中（例如，移植受者、艾滋病患者和老年人）。由于目前治疗剂的窄谱、耐药病毒株的出现以及目前治疗选择的有限毒性，因此确实需要有效且安全地治疗疱疹病毒感染的新药剂，特别是由免疫功能低下患者中的耐药病毒株引起的那些。我们以前已经确定了亚甲基环丙烷核苷（MCPNs）作为HCMV，HHV- 6和HHV-8的有效抑制剂。SBIR I期提案的最初目标是鉴定具有更大抗HHV 6/8效力和功效的新MCPN类似物，同时保持HCMV活性。我们已经超过了SBIR第一阶段的目标，现在已经确定了新的MCPN类似物具有非常不寻常的，广泛的抗疱疹活性谱，包括α，β和γ疱疹病毒，包括ACV耐药株。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发现。本SBIR II期提案的主要目的是在动物模型中评价有限数量的最强效MCPN的鼠毒性、PK/PD和疗效（HSV/CMV/VZV），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，从而推进IND，使大鼠GLP毒理学和安全药理学研究成为可能。

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.