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Rational Design of a Highly Potent and Selective Peptide Inhibitor of PACE4 by Salt Bridge Interaction with D160 at Position P3
Author(s) -
Dianati Vahid,
Shamloo Azar,
Kwiatkowska Anna,
Desjardins Roxane,
Soldera Armand,
Day Robert,
Dory Yves L.
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700300
Subject(s) - proprotein convertases , furin , proteases , salt bridge , serine , serine protease , chemistry , residue (chemistry) , stereochemistry , biochemistry , protease , enzyme , mutant , ldl receptor , gene , lipoprotein , cholesterol
PACE4, a member of the proprotein convertases (PCs) family of serine proteases, is a validated target for prostate cancer. Our group has developed a potent and selective PACE4 inhibitor: Ac‐LLLLRVKR‐NH 2 . In seeking for modifications to increase the selectivity of this ligand toward PACE4, we replaced one of its P3 Val methyl groups with a basic group capable of forming a salt bridge with D160 of PACE4. The resulting inhibitor is eight times more potent than the P3 Val parent inhibitor and two times more selective over furin, because the equivalent salt bridge with furin E257 is not optimal. Moreover, the β‐branched nature of the new P3 residue favors the extended β‐sheet conformation usually associated with substrates of proteases. This work provides new insight for better understanding of β‐sheet backbone–backbone interactions between serine proteases and their peptidic ligands.