New Thrombolytic Agents: Basic Development
Thrombolytic agents are the enzymes that convert plasma protein plasminogen to active protease plasmin, and thus they are called plasminogen activators (PAs). Plasmin thus activated by PAs expresses its proteolytic activity, degrading fibrin (lysis of fibrin, or fibrinolysis) as well as its precursor fibrinogen (lysis of fibrinogen, fibrinogenolysis). Therefore, fibrinolysis is an event that occurs on the solid (fibrin) phase, and fibrinogenolysis is an event in the fluid (plasma) phase. α2-Antiplasmin (α2-AP), a specific inhibitor of plasmin, inactivates plasmin activity by binding to an active center and lysine binding site (LBS) of the enzyme. However, plasmin bound on fibrin is protected from inhibition by α2-AP because plasmin binds to fibrin via LBS, which is not available for binding of α2-AP. Thus, plasmin bound on fibrin expresses its proteolytic activity without any inhibition by α2-AP, resulting in an effective degradation of fibrin. On the other hand, when PAs activate plasminogen to plasmin in circulating plasma, the plasmin is rapidly inactivated by α2-AP. If an excess amount of plasmin is generated in plasma that is not completely blocked by available α2-AP, the residual plasmin still circulates in plasma, causing degradation of several coagulant factors including fibrinogen. This “lytic state” leads to a bleeding tendency. Therefore, it is important to induce plasmin formation on fibrin surface.
KeywordsThrombolytic Agent Anisoylated Plasminogen Streptokinase Activator Complex Kringle Domain Lysine Binding Site Lytic State
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