[Synthetic inhibitors targeting serine and aspartic acid proteases].
The interaction of novel series of synthetic inhibitors with various serine proteases (leukocyte elastase, thrombin, cathepsin G, chymotrypsin, plasminogen activators and plasmin) and an aspartic protease (HIV-1 protease) were studied. Various aspects were analyzed: mechanism of action, structure-activity relationships, and in some cases, molecular modelling and biological evaluation. Functionalized cyclopeptides and N-aryl azetidin-2-ones behaved as suicide substrates acting specifically on trypsin-like proteases (thrombin or urokinase) and elastases, respectively. Novel hydrazinopeptides acted as reversible inhibitors of elastases. Coumarin derivatives inactivated very efficiently chymotrypsin-like proteases (k(inact)/K(I) = 760,000 M(-1) .s(-1)). Inhibitors of HIV-1 protease acting either as inactivators or dimerization inhibitors are under investigation. The inhibitors described above are useful for elucidating the biological roles of the target enzymes and constitute potential drugs.
Reboud-Ravaux
M C
MC
Département de Biologie Supramoléculaire et Cellulaire, Institut Jacques Monod, Université de Paris VII, France. reboud@ccr.jussieu.fr
Boggetto
N D
ND
Doucet
C E
CE
de Rosny
E H
EH
Vergely
I B
IB
Thierry
N M
NM
Amour
A J
AJ
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D006801:Humans; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*
D011480:Protease Inhibitors; D015842:Serine Proteinase Inhibitors; D016282:Aspartic Acid Endopeptidases
Inhibiteurs synthétiques à visée pharmacologique ciblant les protéases à sérine et à acides aspartiques.