A designed P1 cysteine mimetic for covalent and non-covalent inhibitors of HCV NS3 protease

The difluoromethyl group was designed by computational chemistry methods as a mimetic of the canonical P1 cysteine thiol for inhibitors of the hepatitis C virus NS3 protease. This modification led to the development of competitive, non-covalent inhibitor 4 (Ki 30 nM) and reversible covalent inhibitors (6, Ki 0.5 nM; and 8 Ki∗ 10 pM).