Identification of Novel Epoxide Inhibitors of HCV Replication Using a High- Throughput Screen

GI Unit, Department of Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114; Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138; The Broad Institute of Harvard and M.I.T., 7 Cambridge Center, Cambridge, MA 02142; Department of Gastroenterology and Hepatology, Gachon University Gil Medical Center, 1198 Guwol-dong, Namdong-gu, Incheon, 405-760 Korea; Department of Chemistry and Center for Chemical Methodology and Library Development (CMLD-BU), Boston University, 590 Commonwealth Avenue, Boston, MA 02215; Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University; Department of Molecular Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences; Howard Hughes Medical Institute

^* To whom correspondence should be addressed. Email: rtchung{at}partners.org.

	Abstract

Using our high-throughput hepatitis C replicon assay to screen a library of over 8,000 novel diversity-oriented synthesis (DOS) compounds we identified several novel compounds that regulate HCV replication, including 2 libraries of epoxides that inhibit HCV replication (best EC₅₀ < 0.5 µM), and synthesized an analog of these compounds with optimized activity.