Design of Novel Thrombolytic Agents via Domain Modifications* 1

Abstract

Generation of plasmin in the vicinity of a blood clot has proven to be an effective approach for treating thrombotic disorders, particularly myocardial infarction. Conceptually, the ideal thrombolytic agent would initiate the formation of plasmin, primarily in association with fibrin incorporated into the occlusive thrombus. Thus, thrombolytic agents that exhibit relative fibrin specificity and, thus, presumably clot selectivity (e.g., tissue plasminogen activator) were expected to have a marked clinical benefit compared to agents that do not display affinity for fibrin (e.g., streptokinase). However, results obtained recently from clinical trials indicate that these 2 agents essentially were equally effective in treating myocardial infarction. With these findings in mind, efforts are being made to develop novel thrombolytic agents that might achieve more rapid and specific thrombolysis than that achieved by presently available agents and, thus, could be administered earlier because of an improved margin of safety. The available data suggest that tissue-type PA (tPA) mutants possessing resistance to endogenous inhibitors, altered fibrin affinity, and/or slower rates of clearance may prove beneficial in this regard. In addition, adjunctive therapies (i.e., anti-platelet and anti-thrombin compounds) have been found to decrease the time necessary to achieve reperfusion and have reduced rates of reocclusion. These efforts are expected to yield therapeutic agents in the 1990s and beyond that, when administered in combination, would exhibit increased efficacy in the treatment of myocardial infarction and other thrombotic disorders.