Hepatitis C virus (HCV) infects an estimated 150 million people worldwide and is the leading cause of hepatitis, cirrhosis, and liver cancer. In the last 4 years the treatment of HCV genotype 1 infection has been revolutionized, with direct-acting antivirals (DAAs) against essential viral proteins improving the therapeutic options and outcomes. However, with the exception of sofosbuvir, these DAAs have poor efficacy against other HCV genotypes and are susceptible to resistance. To develop a robust therapy, the mechanisms underlying drug resistance and genotypic differences in diverse HCV variants need to be revealed. We have used a multi-disciplinary approach, involving protein crystallography, computational drug design, organic synthesis, and medicinal chemistry, to elucidate the molecular basis of drug resistance against NS3/4A protease inhibitors, explaining in atomic detail how and why drug resistance occurs for leading protease inhibitors in clinical development. Based on the structural insights, we have rationally designed new NS3/4A protease inhibitors with flexible P2 moieties that interact with the invariant catalytic triad and avoid contacts with the S2 subsite residues. Structure-activity exploration of the P2 quinoxaline provided inhibitors that retain low nM potency against major drug resistant variants of HCV. More generally, understanding the underlying mechanisms by which drug resistance occurs can be incorporated in drug development against many quickly evolving disease targets.

Design of hepatitis C virus NS3/4A protease iInhibitors with improved activity against drug resistant variants

250th National Meeting (2015)

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