Engineered Peptide Macrocycles Can Inhibit Matrix Metalloproteinases with High Selectivity. Issue 34 (24th July 2019)

• Record Type: Journal Article
• Authors: Maola, Khan; Wilbs, Jonas; Touati, Jeremy; Sabisz, Michal; Kong, Xu‐Dong; Baumann, Alice; Deyle, Kaycie; Heinis, Christian
• Is Part Of: Angewandte Chemie international edition. Volume 58:Issue 34(2019)
• Page Start: 11801
• Page End: 11805
• Publication Date: 2019-07-24
• Subjects: matrix metalloproteinase -- MMP-2 -- peptides -- phage display -- selectivity; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201906791
• Languages: English
• ISSNs: 1433-7851

Abstract

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 nm ), 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. Abstract : The selective inhibition of individual matrix metalloproteinase has been a great challenge due to high structural conservation in the catalytic domains and shallow substrate binding sites. Herein, we show that inhibitors with high selectivity for specific MMPs can be developed based on peptide macrocycles.