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Antimicrobial Agents and Chemotherapy, June 2008, p. 2043-2052, Vol. 52, No. 6
0066-4804/08/$08.00+0     doi:10.1128/AAC.01548-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Selection of Replicon Variants Resistant to ACH-806, a Novel Hepatitis C Virus Inhibitor with No Cross-Resistance to NS3 Protease and NS5B Polymerase Inhibitors{triangledown}

Wengang Yang, Yongsen Zhao, Joanne Fabrycki, Xiaohong Hou, Xingtie Nie, Amy Sanchez, Avinash Phadke, Milind Deshpande, Atul Agarwal, and Mingjun Huang*

Achillion Pharmaceuticals, New Haven, Connecticut 06511

Received 30 November 2007/ Returned for modification 29 January 2008/ Accepted 4 April 2008

We have discovered a novel class of compounds active against hepatitis C virus (HCV), using a surrogate cellular system, HCV replicon cells. The leading compound in the series, ACH-806 (GS-9132), is a potent and specific inhibitor of HCV. The selection of resistance replicon variants against ACH-806 was performed to map the mutations conferring resistance to ACH-806 and to determine cross-resistance profiles with other classes of HCV inhibitors. Several clones emerged after the addition of ACH-806 to HCV replicon cells at frequencies and durations similar to that observed with NS3 protease inhibitors and NS5B polymerase inhibitors. Phenotypic analyses of these clones revealed that they are resistant to ACH-806 but remain sensitive to other classes of HCV inhibitors. Moreover, no significant change in the susceptibility to ACH-806 was found when the replicon cellular clones resistant to NS3 protease inhibitors and NS5B polymerase inhibitors were examined. Sequencing of the entire coding region of ACH-806-resistant replicon variants yielded several consensus mutations. Reverse genetics identified two single mutations in NS3, a cysteine-to-serine mutation at amino acid 16 and an alanine-to-valine mutation at amino acid 39, that are responsible for the resistance of the replicon variants to ACH-806. Both mutations are located at the N terminus of NS3 where extensive interactions with the central hydrophobic region of NS4A exist. These data provide evidence that ACH-806 inhibits HCV replication by a novel mechanism.

* Corresponding author. Mailing address: Achillion Pharmaceuticals, 300 George Street, New Haven, CT 06511. Phone: (203) 624-7000. Fax: (203) 624-7003. E-mail: mhuang{at}achillion.com

{triangledown} Published ahead of print on 14 April 2008.

Antimicrobial Agents and Chemotherapy, June 2008, p. 2043-2052, Vol. 52, No. 6
0066-4804/08/$08.00+0     doi:10.1128/AAC.01548-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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  • Pawlotsky, J.-M. (2009). Review: Therapeutic implications of hepatitis C virus resistance to antiviral drugs. Therapeutic Advances in Gastroenterology 2: 205-219 [Abstract]  


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