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J. Biol. Chem., Vol. 283, Issue 4, 2167-2175, January 25, 2008

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2'-Deoxy-4'-azido Nucleoside Analogs Are Highly Potent Inhibitors of Hepatitis C Virus Replication Despite the Lack of 2'--Hydroxyl Groups^*

Klaus Klumpp¹, Genadiy Kalayanov, Han Ma, Sophie Le Pogam, Vincent Leveque, Wen-Rong Jiang, Nicole Inocencio, Anniek De Witte, Sonal Rajyaguru, Ezra Tai, Sushmita Chanda, Michael R. Irwin, Christian Sund, Anna Winqist, Tatiana Maltseva, Staffan Eriksson^¶2, Elena Usova^¶2, Mark Smith, Andre Alker^||, Isabel Najera, Nick Cammack, Joseph A. Martin, Nils Gunnar Johansson, and David B. Smith

From the Roche Palo Alto LLC, Palo Alto, California 94304, Medivir AB, SE-141 44 Huddinge, Sweden, the ^¶Department of Anatomy, Physiology and Biochemistry, the Biomedical Centre, Swedish University of Agricultural Sciences, 75123 Uppsala, Sweden, and ^||Hoffman-LaRoche, 4070 Basel, Switzerland

RNA polymerases effectively discriminate against deoxyribonucleotides and specifically recognize ribonucleotide substrates most likely through direct hydrogen bonding interaction with the 2'--hydroxy moieties of ribonucleosides. Therefore, ribonucleoside analogs as inhibitors of viral RNA polymerases have mostly been designed to retain hydrogen bonding potential at this site for optimal inhibitory potency. Here, two novel nucleoside triphosphate analogs are described, which are efficiently incorporated into nascent RNA by the RNA-dependent RNA polymerase NS5B of hepatitis C virus (HCV), causing chain termination, despite the lack of -hydroxy moieties. 2'-Deoxy-2'-β-fluoro-4'-azidocytidine (RO-0622) and 2'-deoxy-2'-β-hydroxy-4'-azidocytidine (RO-9187) were excellent substrates for deoxycytidine kinase and were phosphorylated with efficiencies up to 3-fold higher than deoxycytidine. As compared with previous reports on ribonucleosides, higher levels of triphosphate were formed from RO-9187 in primary human hepatocytes, and both compounds were potent inhibitors of HCV virus replication in the replicon system (IC₅₀ = 171 ± 12 nM and 24 ± 3 nM for RO-9187 and RO-0622, respectively; CC₅₀ >1 mM for both). Both compounds inhibited RNA synthesis by HCV polymerases from either HCV genotypes 1a and 1b or containing S96T or S282T point mutations with similar potencies, suggesting no cross-resistance with either R1479 (4'-azidocytidine) or 2'-C-methyl nucleosides. Pharmacokinetic studies with RO-9187 in rats and dogs showed that plasma concentrations exceeding HCV replicon IC₅₀ values 8-150-fold could be achieved by low dose (10 mg/kg) oral administration. Therefore, 2'--deoxy-4'-azido nucleosides are a new class of antiviral nucleosides with promising preclinical properties as potential medicines for the treatment of HCV infection.

Received for publication, October 30, 2007 , and in revised form, November 13, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

² Supported in part by grants from the Swedish Research Council.

¹ To whom correspondence should be addressed: Roche Palo Alto LLC, 3431 Hillview Ave., Palo Alto, CA 94304. Fax: 650-354-7554; E-mail: Klaus.klumpp{at}roche.com.

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