Simple pseudo-dipeptides with a P2' glutamate: a novel inhibitor family of matrix metalloproteases and other metzincins.
A series of pseudo-peptides with general formula X-l-Glu-NH(2) (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 P(2)' 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.
CEA (Commissariat à l'Energie Atomique), iBiTec-S, Service d'Ingénierie Moléculaire de Protéines (SIMOPRO), CE Saclay, 91191 Gif/Yvette, Cedex, France. laurent.devel@cea.fr
Laurent
L
Devel
Fabrice
F
Beau
Mehdi
M
Amoura
Laura
L
Vera
Evelyne
E
Cassar-Lajeunesse
Sandra
S
Garcia
Bertrand
B
Czarny
Enrico A
EA
Stura
Vincent
V
Dive
D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology*; D018698:Glutamic Acid / Q000737:chemistry*; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013379:Substrate Specificity
D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D018698:Glutamic Acid; D020782:Matrix Metalloproteinases