Fig. 1
NWL inhibitors are irreversible peptide vinyl sulfone inhibitors of Casp6. a Chemical structures of NWL-117 and NWL-154 highlighting the lipophilic moiety, the peptide backbone, and the chemical warhead. b Dose-response curve for NWL-117 (closed circle, IC50 = 192 nM) or NWL-154 (open circle, IC50 = 100 nM) against 20 nM recombinant active site-titrated Casp6. Data represent the mean ± S.D. for three independent experiments. c Schematic representation of the mechanism for covalent linkage of vinyl sulfone warheads to the catalytic cysteine of Casp6. 1 Peptide (VEID) binds to the substrate-binding pocket. 2 This interaction allows the sulfone moiety to form a hydrogen bond with the protonated imidazole ring of histidine. 3 The sulfur from the catalytic cysteine performs a nucleophilic attack on the β-carbon of the vinyl group, which triggers a movement of electrons leading to the protonation of the α-carbon. The result is a covalent link between the vinyl sulfone inhibitor and Casp6