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.
The overall goal of the project is to develop a single agent active against all herpes viruses for use in the immunocompromised patient population. 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) 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.
|Komazin-Meredith, Gloria; Chou, Sunwen; Prichard, Mark N et al. (2014) Human cytomegalovirus UL97 kinase is involved in the mechanism of action of methylenecyclopropane analogs with 6-ether and -thioether substitutions. Antimicrob Agents Chemother 58:274-8|
|Chou, Sunwen; Komazin-Meredith, Gloria; Williams, John D et al. (2014) Cytomegalovirus mutants resistant to ganciclovir and cidofovir differ in susceptibilities to synguanol and its 6-ether and 6-thioether derivatives. Antimicrob Agents Chemother 58:1809-12|
|Komazin-Meredith, Gloria; Cardinale, Steven C; Williams, John D et al. (2013) Human herpesvirus 6 U69 kinase phosphorylates the methylenecyclopropane nucleosides cyclopropavir, MBX 2168, and MBX 1616 to their monophosphates. Antimicrob Agents Chemother 57:5760-2|