Simple Pseudo-dipeptides with a P2′ Glutamate

• Published in: The Journal of biological chemistry 2012-08, Vol.287 (32), p.26647-26656
• Main Authors: Devel, Laurent, Beau, Fabrice, Amoura, Mehdi, Vera, Laura, Cassar-Lajeunesse, Evelyne, Garcia, Sandra, Czarny, Bertrand, Stura, Enrico A., Dive, Vincent
• Format: Article
• Language: English
• Subjects: ADAM ADAMTS; Crystal Structure; Drug Design; Enzyme Inhibitors; Matrix Metalloproteinase (MMP)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M112.380782

A series of pseudo-peptides with general formula X-l-Glu-NH2 (with X corresponding to an acyl moiety with a long aryl-alkyl side chain) have been synthesized, evaluated as inhibitors of matrix metalloproteases (MMPs), and found to display remarkable nanomolar affinity. The loss in potency associated with a substitution of the P2′ l-glutamate by a l-glutamine corroborates the importance of a carboxylate at this position. The binding mode of some of these inhibitors was characterized in solution and by x-ray crystallography in complex with various MMPs. The x-ray crystal structures reveal an unusual binding mode with the glutamate side chain chelating the active site zinc ion. Competition experiments between these inhibitors and acetohydroxamic acid, a small zinc-binding molecule, are in accord with the crystallographic results. One of these pseudo-dipeptides displays potency and selectivity toward MMP-12 similar to the best MMP-12 inhibitors reported to date. This novel family of pseudo peptides opens new opportunities to develop potent and selective inhibitors for several metzincins. Background: MMP inhibitor design relies on the use of peptidic or non-peptidic scaffolds with a zinc-chelating function. Results: Pseudo-dipeptides containing a l-glutamate motif are potent MMP inhibitors. Conclusion: The l-glutamate scaffold is exploitable to develop potent inhibitors of metzincins. Significance: A new family of zinc protease inhibitors has been discovered.