Functional properties of a novel mutant of staphylokinase with platelet-targeted fibrinolysis and antiplatelet aggregation activities

• Published in: European journal of pharmacology Vol. 566; no. 1; pp. 137 - 144
• Main Authors: Chen, Hongshan, Mo, Wei, Zhang, Yanling, Su, Huabo, Ma, Janying, Yao, Ruiming, Zhang, Shaoheng, Ge, Junbo, Song, Houyan
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 02.07.2007; Elsevier
• Subjects: Animals; Antiplatelet activity; Biological and medical sciences; Coronary Thrombosis - drug therapy; Coronary Thrombosis - physiopathology; Fibrin - metabolism; Fibrinolysis; Humans; Medical sciences; Metalloendopeptidases - genetics; Metalloendopeptidases - metabolism; Metalloendopeptidases - pharmacology; Mutation; Pharmacology. Drug treatments; Plasminogen - metabolism; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - pharmacology; Platelet-targeted fibrinolysis; RGD motif; Staphylokinase; Swine; Staphylokinase; RGD motif; Antiplatelet activity; Platelet-targeted fibrinolysis; Target; Platelet; Mutation; Fibrinolysis; Antiplatelet agent
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2007.03.010

The present study was performed to characterize the functional properties of RGD-SAK, a novel mutant of staphylokinase (SAK). Biochemical analysis indicated that RGD-SAK maintained the similar structure and the fibrinolytic function of SAK. Measurement of platelet binding activity in vitro demonstrated that RGD-SAK had a much higher affinity with platelets than SAK. In vitro platelet-rich clot lysis assay demonstrated that the engineered mutant outperformed the non-manipulated SAK. The time required for 50% platelet-rich clot lysis was reduced significantly across different concentrations of RGD-SAK comparing with SAK. Meanwhile, RGD-SAK was found to inhibit ADP-induced platelet aggregation in a concentration-dependent manner while SAK had negligible effect on platelet aggregation. In concordance, further study in a porcine coronary balloon injury model demonstrated the efficacy of RGD-SAK for the lysis of platelet-rich coronary blood clots and for the prevention of reocclusion after thrombolysis. These results suggested that RGD-SAK may serve as a potential thrombolytic agent with platelet-targeted fibrinolysis and antiplatelet aggregation activities.