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八个成员，分为三个亚科，指定为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）。乙型疱疹病毒包括人类巨细胞病毒（HCMV）、人类疱疹病毒6的两种变体（HHV-6A、HHV-6B）和人类疱疹病毒7 （HHV-7）。伽玛疱疹病毒包括eb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，许多人存在重大的健康问题，特别是在免疫功能低下的患者群体中（例如，移植受者、艾滋病患者和老年人）。由于目前治疗方法的范围狭窄，耐药病毒株的出现，以及目前治疗方案的有限毒性，明确需要有效和安全的新药物来治疗疱疹病毒感染，特别是免疫功能低下患者中由耐药病毒株引起的感染。我们之前已经发现亚甲基环丙烷核苷（MCPNs）是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新的MCPN类似物，具有更强的抗hhv6 /8效力和疗效，同时保持HCMV活性。我们已经超过了SBIR I期目标，并且现在已经确定了具有非常不寻常的，广泛的抗疱疹活性的新型MCPN类似物，包括α， β和γ -疱疹病毒，包括ACV抗性菌株。据我们所知，现有的抗疱疹病毒药物尚未发现这种广谱活性。SBIR II期计划的主要目标是在动物模型中评估有限数量的最有效的mcpn在小鼠毒性、PK/PD和功效（HSV/CMV/VZV）方面的作用，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大鼠GLP毒理学和安全药理学研究。

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.