Enhancement of fibrinolysis by inhibiting enzymatic cleavage of precursor α2-antiplasmin.

摘要: Background and objective Resistance of thrombi to plasmin digestion depends primarily on the amount α(2)-antiplasmin (α(2)AP) incorporated within fibrin. Circulating prolyl-specific serine proteinase, antiplasmin-cleaving enzyme (APCE), a homologue fibroblast activation protein (FAP), cleaves precursor Met-α(2)AP between -Pro12-Asn13- yield Asn-α(2)AP, which is crosslinked fibrin approximately 13× more rapidly than confers resistance plasmin. We reasoned that an APCE inhibitor might decrease conversion Asn-α(2)AP thereby enhance endogenous fibrinolysis. Methods results designed synthesized several inhibitors assessed each vs. plasma dipeptidyl peptidase IV (DPPIV) prolyl oligopeptidase (POP), have amino acid sequence similarity with APCE. Acetyl-Arg-(8-amino-3,6-dioxaoctanoic acid)-D-Ala-L-boroPro selectively inhibited DPPIV, apparent K(i) 5.7 nm 6.1 μm, indicating 1000-fold greater concentration required for DPPIV An 7.4 was found POP inhibition, similar APCE; however, potential problem overlapping FAP/APCE inhibition negated by our finding normal human lacks activity. The construct caused dose-dependent APCE-mediated cleavage, ultimately shortened plasminogen activator-induced clot lysis times. Incubation 22 h did not lessen its inhibitory activity, IC(50) value in remaining comparable phosphate buffer. Conclusion These data establish represent therapeutic approach enhancing thrombolytic