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Antimicrobial Agents and Chemotherapy, August 2003, p. 2674-2681, Vol. 47, No. 8
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.8.2674-2681.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Dinucleotide Analogues as Novel Inhibitors of RNA-Dependent RNA Polymerase of Hepatitis C Virus

Weidong Zhong,* Haoyun An, Dinesh Barawkar, and Zhi Hong

Drug Discovery, Ribapharm, Inc., Costa Mesa, California 92626

Received 5 March 2003/ Returned for modification 12 May 2003/ Accepted 23 May 2003

Replication of hepatitis C virus (HCV) RNA is catalyzed by the virally encoded RNA-dependent RNA polymerase NS5B. It is believed that the viral polymerase utilizes a de novo or primer-independent mechanism for initiation of RNA synthesis. Our previous work has shown that dinucleotides were efficient initiation molecules for NS5B in vitro (W. Zhong, E. Ferrari, C. A. Lesburg, D. Maag, S. K. Ghosh, C. E. Cameron, J. Y. Lau, and Z. Hong, J. Virol. 74:9134-9143, 2000). In this study, we further demonstrated that dinucleotide analogues could serve as inhibitors of de novo initiation of RNA synthesis directed by HCV NS5B. Both mononucleotide- and dinucleotide-initiated RNA syntheses were affected by dinucleotide analogues. The presence of the 5'-phosphate group in the dinucleotide compounds was required for efficient inhibition of de novo initiation. Optimal inhibitory activity also appeared to be dependent on the base-pairing potential between the compounds and the template terminal bases. Because the initiation process is a rate-limiting step in viral RNA replication, inhibitors that interfere with the initiation process will have advantages in suppressing virus replication. The use of dinucleotide analogues as inhibitor molecules to target viral replication initiation represents a novel approach to antiviral interference.

* Corresponding author. Mailing address: Ribapharm, Inc., 3300 Hyland Ave., Costa Mesa, CA 92626. Phone: (714) 427-6236, ext. 2201. Fax: (714) 668-3141. E-mail: wzhong{at}ribapharm.com.

Antimicrobial Agents and Chemotherapy, August 2003, p. 2674-2681, Vol. 47, No. 8
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.8.2674-2681.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.





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