Abstract
From l-α-aminobutyric acid (Abu) a set of electrophilic and non-electrophilic replacements for the P1 cysteine of substrate and product inhibitors of hepatitis C virus full-length NS3 (protease-helicase/NTPase) serine protease have been synthesised and coupled to a model pentapeptide furnishing a set of hexapeptide inhibitors. Promising inhibitory activities with Ki values of 0.18μM (11b, P1 electrophilic α,β-unsaturated ketone), 0.46μM (12e, P1 electrophilic alkyl ketone) and 0.98μM (10e, P1 non-electrophilic alkenyl alcohol as diastereomeric mixture). The reference hexapeptide product inhibitor had a Ki value of 1.54μM (14, P1 Abu–OH). The electrophilic inhibitors exhibit increased potency as compared with the corresponding product inhibitor, and notably also the non-electrophilic P1 alkenyl alcohol 10e. This represents the first example of non-electrophilic inhibitors that are not P1 amides or product inhibitors.
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