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Engineered Peptide Macrocycles Can Inhibit Matrix Metalloproteinases with High Selectivity
Author(s) -
Maola Khan,
Wilbs Jonas,
Touati Jeremy,
Sabisz Michal,
Kong XuDong,
Baumann Alice,
Deyle Kaycie,
Heinis Christian
Publication year - 2019
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201906791
Subject(s) - matrix metalloproteinase , peptide , selectivity , combinatorial chemistry , chemistry , stereochemistry , biochemistry , catalysis
Abstract Matrix metalloproteinases (MMPs) are zinc‐dependent endopeptidases at the intersection of health and disease due to their involvement in processes such as tissue repair and immunity as well as cancer and inflammation. Because of the high structural conservation in the catalytic domains and shallow substrate binding sites, selective, small‐molecule inhibitors of MMPs have remained elusive. In a tour‐de‐force peptide engineering approach combining phage‐display selections, rational design of enhanced zinc chelation, and d ‐amino acid screening, we succeeded in developing a first synthetic MMP‐2 inhibitor that combines high potency ( K i =1.9±0.5 n m ), high target selectivity, and proteolytic stability, and thus fulfills all the required qualities for in cell culture and in vivo application. Our work suggests that selective MMP inhibition is achievable with peptide macrocycles and paves the way for developing specific inhibitors for application as chemical probes and potentially therapeutics.