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Antimicrobial Agents and Chemotherapy, June 2009, p. 2660-2662, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.01546-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Octadecyloxyethyl Ester of (S)-9-[3-Hydroxy-2-(Phosphonomethoxy) Propyl]Adenine Is a Potent and Selective Inhibitor of Hepatitis C Virus Replication in Genotype 1A, 1B, and 2A Replicons{triangledown}

David L. Wyles,1 Kelly A. Kaihara,1 Brent E. Korba,1,2 Robert T. Schooley,1 James R. Beadle,1 and Karl Y. Hostetler1*

San Diego Veterans Medical Research Foundation and the Department of Medicine, Division of Infectious Disease, University of California, San Diego, La Jolla, California 92093-0676,1 Division of Molecular Virology and Immunology, Georgetown University Medical Center, Rockville, Maryland 208502

Received 19 November 2008/ Returned for modification 24 December 2008/ Accepted 11 March 2009

The octadecyloxyethyl (ODE) and hexadecyloxypropyl (HDP) esters of (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine (HPMPA) are potent inhibitors of orthopoxvirus, herpesvirus, human immunodeficiency virus type 1, and hepatitis B virus replication in vitro. HDP and ODE esters of (S)-HPMPA and (R)-HPMPA were evaluated for their activity in hepatitis C virus (HCV) replicon assays using luciferase (1B and 2A replicons) or RNA (1B) quantification. The ODE ester of (S)-HPMPA [ODE-(S)-HPMPA] was the most active compound, with 50% effective concentrations (EC50s) in the 0.69 to 1.31 µM range. HDP and ODE esters of (R)-HPMPA were severalfold less active, while (S)-HPMPA and (R)-HPMPA were inactive. In genotype 1A and 1B replicons analyzed by HCV RNA analysis, ODE-(S)-HPMPA was the most active compound, with EC50s of 1.8 and 2.1 µM, respectively.

* Corresponding author. Mailing address: Department of Medicine, Division of Infectious Disease (0676), University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0676. Phone: (858) 552-8585, ext. 2616. Fax: (858) 534-6133. E-mail: khostetler{at}ucsd.edu

{triangledown} Published ahead of print on 16 March 2009.

Antimicrobial Agents and Chemotherapy, June 2009, p. 2660-2662, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.01546-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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