Treatment of Cytomegalovirus by Inhibition of Host Lipid Synthesis

DESCRIPTION (provided by applicant): Cytomegalovirus (CMV) causes significant disease and mortality in populations with weakened immune systems, including cancer patients, organ transplant recipients, and HIV-infected people. Additionally, it is the most common cause of congenital infection affecting about 1% of all live births worldwide, causing 20-30% of infants infected in utero to develop birth defects. Marketed CMV antivirals such as ganciclovir cause fever, diarrhea, and/or leukopenia in the majorityof treated adults, and are teratogenic in pregnancy. To address the unmet clinical need for a more safe and effective CMV treatment, Kadmon Corporation is working towards development of a novel class of antivirals that target host cell metabolic lipid metabolism, upon which the virus depends, with primary efforts examining small molecule inhibitors of Acetyl- CoA Carboxylase (ACC). We have shown that three separate small molecules that inhibit ACC block CMV replication in vitro in a dose dependent manner. This project proposes: (1) further studies of the efficacy of ACC inhibitors in vitro, against clinical isolates of CMV and mouse or guinea pig CMV; (2) metabolomic studies to identify metabolic correlates of anti-CMV efficacy; and (3) in vivo efficacy studies in animal models of CMV infection. Together these studies will validate ACC as a target for anti-CMV therapy, the overarching aim of this Phase I SBIR. The general strategy in SBIR Phase II will be to optimize an ACC inhibitor's pharmacology and to complete necessary preclinical experiments to enable IND filing. With respect to clinical development and commercialization, the initial indication will be for treatment of CMV disease in immune-compromised adults. In the long term, there is the potential also to provide a much- needed treatment for congenital CMV infection. PUBLIC HEALTH RELEVANCE: Cytomegalovirus (CMV) CMV infection is asymptomatic for most people, but the virus causes significant disease and mortality in populations with weakened immune systems, including cancer patients, organ transplant recipients, and HIV-infected people, and is the most common cause of congenital infection affecting about 1% of all live births worldwide. The present project proposes to demonstrate proof-of-concept efficacy of host cell lipid metabolism as a novel target for anti-CMV therapy.