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Antimicrobial Agents and Chemotherapy, February 2008, p. 458-464, Vol. 52, No. 2
0066-4804/08/$08.00+0     doi:10.1128/AAC.01184-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The Mechanism of Action of β-D-2'-Deoxy-2'-Fluoro-2'-C-Methylcytidine Involves a Second Metabolic Pathway Leading to β-D-2'-Deoxy-2'-Fluoro-2'-C-Methyluridine 5'-Triphosphate, a Potent Inhibitor of the Hepatitis C Virus RNA-Dependent RNA Polymerase{triangledown}

Eisuke Murakami, Congrong Niu, Haiying Bao, Holly M. Micolochick Steuer, Tony Whitaker,{dagger} Tammy Nachman, Michael A. Sofia, Peiyuan Wang, Michael J. Otto, and Phillip A. Furman*

Pharmasset, Inc., 303 A College Road East, Princeton, New Jersey 08540

Received 7 September 2007/ Returned for modification 12 October 2007/ Accepted 30 October 2007

β-D-2'-Deoxy-2'-fluoro-2'-C-methylcytidine (PSI-6130) is a potent inhibitor of hepatitis C virus (HCV) RNA replication in an HCV replicon assay. The 5'-triphosphate of PSI-6130 is a competitive inhibitor of the HCV RNA-dependent RNA polymerase (RdRp) and acts as a nonobligate chain terminator. Recently, it has been shown that the metabolism of PSI-6130 also results in the formation of the 5'-triphosphate of the uridine congener, β-D-2'-deoxy-2'-fluoro-2'-C-methyluridine (PSI-6206; RO2433). Here we show that the formation of the 5'-triphosphate of RO2433 (RO2433-TP) requires the deamination of PSI-6130 monophosphate and that RO2433 monophosphate is subsequently phosphorylated to the corresponding di- and triphosphates by cellular UMP-CMP kinase and nucleoside diphosphate kinase, respectively. RO2433-TP is a potent inhibitor of the HCV RdRp; however, both enzymatic and cell-based assays show that PSI-6130 triphosphate is a more potent inhibitor of the HCV RdRp than RO2433-TP.

* Corresponding author. Mailing address: Pharmasset, Inc., 303 A College Road East, Princeton, NJ 08540. Phone: (609) 613-4100. Fax: (609) 613-4150. E-mail: phillip.furman{at}pharmasset.com

{triangledown} Published ahead of print on 12 November 2007.

{dagger} Present address: RFS Pharma LLC, 1860 Montreal Road, Tucker, GA 30084.

Antimicrobial Agents and Chemotherapy, February 2008, p. 458-464, Vol. 52, No. 2
0066-4804/08/$08.00+0     doi:10.1128/AAC.01184-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Ali, S., Leveque, V., Le Pogam, S., Ma, H., Philipp, F., Inocencio, N., Smith, M., Alker, A., Kang, H., Najera, I., Klumpp, K., Symons, J., Cammack, N., Jiang, W.-R. (2008). Selected Replicon Variants with Low-Level In Vitro Resistance to the Hepatitis C Virus NS5B Polymerase Inhibitor PSI-6130 Lack Cross-Resistance with R1479. Antimicrob. Agents Chemother. 52: 4356-4369 [Abstract] [Full Text]  


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