Resistance outside the substrate envelope: hepatitis C NS3/4A protease inhibitors

Abstract

Direct acting antivirals have dramatically increased the efficacy and tolerability of hepatitis C treatment, but drug resistance has emerged with some of these inhibitors, including nonstructural protein 3/4 A protease inhibitors (PIs). Although many co-crystal structures of PIs with the NS3/4A protease have been reported, a systematic review of these crystal structures in the context of the rapidly emerging drug resistance especially for early PIs has not been performed. To provide a framework for designing better inhibitors with higher barriers to resistance, we performed a quantitative structural analysis using co-crystal structures and models of HCV NS3/4A protease in complex with natural substrates and inhibitors. By comparing substrate structural motifs and active site interactions with inhibitor recognition, we observed that the selection of drug resistance mutations correlates with how inhibitors deviate from viral substrates in molecular recognition. Based on this observation, we conclude that guiding the design process with native substrate recognition features is likely to lead to more robust small molecule inhibitors with decreased susceptibility to resistance.

Keywords:

• Drug resistance
• protease inhibitors
• hepatitis C
• NS34/A protease
• substrate envelope
• structure-based drug design
• resistance mutations

Acknowledgment

We thank Dr. Nese Kurt Yilmaz for assistance.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the National Institute of Allergy and Infectious Disease [R01-AI085051]. DIS was supported by National Institute of General Medical Sciences of the NIH [F31-GM103259]. ANM was supported by National Institute of General Medical Sciences of the [F31-GM119345].