Phosphinic pseudo-tripeptides as potent inhibitors of matrix metalloproteinases: a structure-activity study.
Several phosphinic pseudo-tripeptides of general formula R-XaaPsi(PO(2)-CH(2))Xaa'-Yaa'-NH(2) were synthesized and evaluated for their in vitro activities to inhibit stromelysin-3, gelatinases A and B, membrane type-1 matrix metalloproteinase, collagenases 1 and 2, and matrilysin. With the exception of collagenase-1 and matrilysin, phosphinic pseudo-tripeptides behave as highly potent inhibitors of matrix metalloproteinases, provided they contain in P(1)' position an unusual long aryl-alkyl substituent. Study of structure-activity relationships regarding the influence of the R and Xaa' substituents in this series may contribute to the design of inhibitors able to block only a few members of the matrix metalloproteinase family.
CEA, Département d'Ingénierie et d'Etudes des Protéines, 91191 Gif/Yvette Cedex, France.
S
S
Vassiliou
A
A
Mucha
P
P
Cuniasse
D
D
Georgiadis
K
K
Lucet-Levannier
F
F
Beau
R
R
Kannan
G
G
Murphy
V
V
Knäuper
M C
MC
Rio
P
P
Basset
A
A
Yiotakis
V
V
Dive
D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D010720:Phosphines / Q000138:chemical synthesis* / Q000737:chemistry; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
D009842:Oligopeptides; D010720:Phosphines; D011480:Protease Inhibitors; D008666:Metalloendopeptidases