Mor A, Reboud-Ravaux M, Mazaleyrat J P, Wakselman M
Institut Jacques Monod, Université de Paris VII, France.
Thromb Res Suppl. 1988;8:35-44. doi: 10.1016/0049-3848(88)90152-1.
Halomethylated derivatives of dihydrocoumarins are efficient enzyme-activated inhibitors ("suicide" substrates) of plasminogen activators. Kinetic analysis indicate that the one-chain and two-chain forms of the human plasminogen activator are inhibited by 3,4-dihydro-3-benzyl-6-chloromethylcoumarin through a mechanism-based inactivation characterized by the following kinetic parameters (4 degrees C, pH 6.8) : k2 equal to 0.02 s-1 and 0.03 s-1 (for one- and two-chain tissue plasminogen activators, respectively) and Ki equal to 0.16 mM for both forms. Human urokinase and human tissue-type plasminogen activator can be discriminated on the basis of their inhibition by this suicide substrate. The design of a new series of suicide substrates of serine proteases (functionalized cyclopeptides possessing a potential alkylating function closely related to that found in halomethylated derivatives of dihydrocoumarins) is described.
二氢香豆素的卤甲基化衍生物是纤溶酶原激活剂的高效酶激活抑制剂（“自杀”底物）。动力学分析表明，人纤溶酶原激活剂的单链和双链形式被3,4-二氢-3-苄基-6-氯甲基香豆素通过基于机制的失活所抑制，其特征在于以下动力学参数（4℃，pH 6.8）：k2分别等于0.02 s-1和0.03 s-1（对于单链和双链组织纤溶酶原激活剂），两种形式的Ki均等于0.16 mM。人尿激酶和人组织型纤溶酶原激活剂可以根据它们被这种自杀底物抑制的情况进行区分。本文描述了一系列新型丝氨酸蛋白酶自杀底物的设计（具有与二氢香豆素卤甲基化衍生物中发现的潜在烷基化功能密切相关的功能化环肽）。
