Rational Design of a Highly Potent and Selective Peptide Inhibitor of PACE4 by Salt Bridge Interaction with D160 at Position P3

摘要: PACE4, a member of the proprotein convertases (PCs) family serine proteases, is validated target for prostate cancer. Our group has developed potent and selective PACE4 inhibitor: Ac-LLLLRVKR-NH2 . In seeking modifications to increase selectivity this ligand toward we replaced one its P3 Val methyl groups with basic capable forming salt bridge D160 PACE4. The resulting inhibitor eight times more than parent two over furin, because equivalent furin E257 not optimal. Moreover, β-branched nature new residue favors extended β-sheet conformation usually associated substrates proteases. This work provides insight better understanding backbone-backbone interactions between proteases their peptidic ligands.