Evaluation of a multifunctional staphylokinase variant with thrombin inhibition and antiplatelet aggregation activities produced from salt-inducible E. coli GJ1158
Translational study published in Canadian Journal of Physiology and Pharmacology (2013)
Abstract
Reocclusion is one of the major root causes for secondary complications that arise during thrombolytic therapy. A multifunctional staphylokinase variant SRH (staphylokinase (SAK) linked with tripeptide RGD and didecapeptide Hirulog) with antiplatelet and antithrombin activities in addition to clot specific thrombolytic function, was developed to address the reocclusion problem. We preferred to use Escherichia coli GJ1158 as the host in this study for economic production of SRH by osmotic (0.3 mol/L sodium chloride) induction, to overcome the problems associated with the yeast expression system. The therapeutic potential of SRH was evaluated in the murine model of vascular thrombosis. The SAK protein (1 mg/kg body mass) and SRH protein (1 mg/kg and 2 mg/kg) were administered intravenously to the different treatment groups. The results have shown a dose-dependent antithrombotic effect in carrageenan-induced mouse tail thrombosis. The thrombin time, activated partial thromboplastin time, and prothrombin time were significantly prolonged (p < 0.05) in the SRH-infused groups. Moreover, SRH inhibited platelet aggregation in a dose-dependent manner (p < 0.05), while the bleeding time was significantly (p < 0.05) prolonged. All of these results inferred that the osmotically produced multifunctional fusion protein SRH (SAK-RGD-Hirulog) is a promising thrombolytic agent, and one which sustained its multifunctionality in the animal models.
Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.
Zusammenfassung
Multifunctional SRH fusion (staphylokinase-RGD-hirulog) had antithrombin, antiplatelet, and clot-specific thrombolytic activity in a murine carrageenan vascular thrombosis model and significantly prolonged aPTT/PT/TT/bleeding time.
Warum dies für die Hirudotherapie relevant ist
This study developed a multifunctional fusion protein SRH (staphylokinase linked with RGD tripeptide and Hirulog didecapeptide) produced via salt-inducible expression in E. coli GJ1158, combining thrombolytic, antithrombin, and antiplatelet activities to address reocclusion during thrombolytic therapy. In a carrageenan-induced mouse tail thrombosis model, SRH showed dose-dependent antithrombotic effects, significantly prolonged thrombin time, aPTT, and prothrombin time (P<0.05), and inhibited platelet aggregation, though bleeding time was also significantly prolonged. The Hirulog component provides a direct link to the hirudin family of thrombin inhibitors. However, this is a preclinical animal study of an engineered recombinant fusion protein; it is not a study of leech therapy or the leech secretome, and the hirudin-derived element is one functional domain within a multi-component construct.
Zitation
Evaluation of a multifunctional staphylokinase variant with thrombin inhibition and antiplatelet aggregation activities produced from salt-inducible E. coli GJ1158.
Kumar A et al. · Canadian Journal of Physiology and Pharmacology, 2013
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