Development of selective inhibitors and substrate of matrix metalloproteinase-12.
Four phosphinic peptide libraries with compounds having the general formula p-Br-Ph-(PO2-CH2)-Xaa'-Yaa'-Zaa'-NH2 have been prepared and screened against 10 matrix metalloproteinases (MMPs). We identified two phosphinic peptides with Ki values of 0.19 and 4.4 nM toward MMP-12 (macrophage elastase) that are more than 2-3 orders of magnitude less potent toward the other MMPs tested. These highly selective MMP-12 inhibitors contain a Glu-Glu motif in their Yaa'-Zaa' positions. Incorporation of this Glu-Glu motif into the sequence of a nonspecific fluorogenic peptide cleaved by MMPs provides a highly selective substrate for MMP-12. A model of one of these inhibitors interacting with MMP-12 suggests that the selectivity observed might be due, in part, to the presence of two unique polar residues in MMP-12, Thr239 and Lys177. These MMP-12-selective inhibitors may have important therapeutic applications to diseases in which MMP-12 has been suggested to play a key role, such as in emphysema, atherosclerosis, and aortic abdominal aneurysm.
Devel
Laurent
L
Commissariat à l'Energie Atomique, Département d'Ingénierie et d'Etudes des Protéines Bat 152, CE-Saclay, 91191 Gif/Yvette, Cedex, France.
Rogakos
Vassilis
V
David
Arnaud
A
Makaritis
Anastasios
A
Beau
Fabrice
F
Cuniasse
Philippe
P
Yiotakis
Athanasios
A
Dive
Vincent
V
D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry; D018698:Glutamic Acid / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D008239:Lysine / Q000737:chemistry; D053508:Matrix Metalloproteinase 12; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000502:physiology; D008956:Models, Chemical; D008958:Models, Molecular; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity; D013912:Threonine / Q000737:chemistry; D013997:Time Factors
D004791:Enzyme Inhibitors; D019151:Peptide Library; D010455:Peptides; D013912:Threonine; D018698:Glutamic Acid; D020782:Matrix Metalloproteinases; D008666:Metalloendopeptidases; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12; D008239:Lysine