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Antimicrobial Agents and Chemotherapy, October 2007, p. 3756-3759, Vol. 51, No. 10
0066-4804/07/$08.00+0     doi:10.1128/AAC.00233-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Identification of Novel Epoxide Inhibitors of Hepatitis C Virus Replication Using a High-Throughput Screen{triangledown} ,{dagger} ,§

Lee F. Peng ,1,2,3,{ddagger} Sun Suk Kim,1,4,{ddagger} Sirinya Matchacheep,2,3 Xiaoguang Lei,5 Shun Su,5 Wenyu Lin,1 Weerawat Runguphan,2,3 Won-Hyeok Choe,1 Naoya Sakamoto,6 Masanori Ikeda,7 Nobuyuki Kato,7 Aaron B. Beeler,5 John A. Porco Jr.,5 Stuart L. Schreiber,2,3,8 and Raymond T. Chung1*

GI Unit, Department of Medicine, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114,1 Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138,2 The Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02142,3 Department of Gastroenterology and Hepatology, Gachon University Gil Medical Center, 1198 Guwol-dong, Namdong-gu, Incheon, 405-760 Korea,4 Department of Chemistry and Center for Chemical Methodology and Library Development (CMLD-BU), Boston University, 590 Commonwealth Avenue, Boston, Massachusetts 02215,5 Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan,6 Department of Molecular Biology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan,7 Howard Hughes Medical Institute, Chevy Chase, Maryland8

Received 15 February 2007/ Returned for modification 7 May 2007/ Accepted 28 July 2007

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 hepatitis C virus (HCV) replication, including two libraries of epoxides that inhibit HCV replication (best 50% effective concentration, < 0.5 µM). We then synthesized an analog of these compounds with optimized activity.

* Corresponding author. Mailing address: GRJ 825A, GI Unit, Massachusetts General Hospital, Boston, MA 02114. Phone: (617) 724-7562. Fax: (617) 726-5895. E-mail: rtchung{at}partners.org

{triangledown} Published ahead of print on 6 August 2007.

{dagger} This publication is dedicated to Yoshito Kishi on the occasion of his 70th birthday.

§ Supplemental material for this article may be found at http://aac.asm.org/.

{ddagger} L.F.P. and S.S.K. contributed equally to this project.

Antimicrobial Agents and Chemotherapy, October 2007, p. 3756-3759, Vol. 51, No. 10
0066-4804/07/$08.00+0     doi:10.1128/AAC.00233-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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