Reboud-Ravaux M C, Boggetto N D, Doucet C E, de Rosny E H, Vergely I B, Thierry N M, Amour A J
Département de Biologie Supramoléculaire et Cellulaire, Institut Jacques Monod, Université de Paris VII, France.
J Pharm Belg. 1996 May-Jun;51(3):161-4.
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.
研究了一系列新型合成抑制剂与各种丝氨酸蛋白酶（白细胞弹性蛋白酶、凝血酶、组织蛋白酶G、胰凝乳蛋白酶、纤溶酶原激活剂和纤溶酶）以及一种天冬氨酸蛋白酶（HIV-1蛋白酶）的相互作用。分析了多个方面：作用机制、构效关系，在某些情况下还进行了分子建模和生物学评估。功能化环肽和N-芳基氮杂环丁烷-2-酮分别作为自杀底物，特异性作用于胰蛋白酶样蛋白酶（凝血酶或尿激酶）和弹性蛋白酶。新型肼肽作为弹性蛋白酶的可逆抑制剂。香豆素衍生物能非常有效地使胰凝乳蛋白酶样蛋白酶失活（k(inact)/K(I)=760,000 M(-1)·s(-1)）。作为失活剂或二聚化抑制剂的HIV-1蛋白酶抑制剂正在研究中。上述抑制剂有助于阐明靶酶的生物学作用，并构成潜在药物。
