Human cytomegalovirus (HCMV) infections continue to represent a major health concern in the immunocompromised population, especially recipients of bone marrow and solid-organ transplants. HCMV remains an important cause of congenital viral infection associated with deafness, mental retardation and mortality. Current therapy, which includes ganciclovir (GCV), cidofovir (CDV) and foscarnet (PFA), all suffer from dose-related toxicities, including neutropenia and nephrotoxicity, poor oral bioavailability and the development of drug resistant viral mutants. Therefore, the need is high for new orally active less toxic anti- HCMV agents. The methylenecyclopropane (MP) compounds are new anti-viral agents that have shown excellent anti-HCMV activity in vitro and in vivo. Based upon progress in the SBIR Phase I research plan, a lead MP compound, ZSM-l-62, has been chosen as a clinical-candidate for further Investigational New Drug (IND) enabling studies (SBIR Phase II application). ZSM-l-62 has been shown to prevent HCMV replication (5 log10 reduction, IC50 = 0.16muM), including GCV and PFA resistant virus. ZSM-l-62 (1-10 mg/kg) is orally active, 58% oral bioavailability, in two murine CMV (MCMV) models and two HCMV infection models in SCID-hu mice. ZSM-l-62 was superior to GCV and reduced mortality even when treatment was delayed 72 hrs. after viral inoculation and when GCV was without effect. ZSM-l-62 treatment resulted in a 3-5log10 decrease in liver, spleen and kidney virus titers. ZSM-l-62 was less toxic that GCV to human bone marrow cells and non-toxic in mice up to the highest dose tested (45 mg/kg, p.o., once a day for 28 days). An analytical method has been developed to measure ZSM-l-62 in body fluids and an improved chemical synthesis is now available to produce material for preclinical studies. The goal of the SBIR Phase II is to complete IND enabling preclinical toxicology and safety pharmacology studies and file an IND by the end of the two year SBIR for ZSM-l-62 for the treatment of HCMV infection. ZSM-l-62 has also shown good activity (EC50=0.7-7.8(iM) against other betaherpesviruses (e.g. HHV-6) and gammaherpesviruses (e.g. HHV-8). Therefore, the possibility exists that ZSM-l-62 may have broader activity and advantages against multiple viral pathogens in the immunocompromised host. The activity of ZSM-l-62 against these pathogens will be furthered explored and can be included in any future human clinical trial.
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