Role of isopeptidolysis in the process of thrombolysis

INTRODUCTION: Known thrombolytic agents either break peptide bonds in the fibrin molecule or act as plasminogen activators, which also results in peptide bond cleavage. In thrombi, fibrin molecules are known to be cross-linked by isopeptide bonds, the formation of which is mediated by factor XIIIa. In this work, we studied the dissolution of thrombi via isopeptide bond cleavage using a recombinant destabilase. Destabilase is an enzyme secreted from the medicinal leech salivary gland. This enzyme exhibits muramidase (lysozyme) activity, in addition to endo-ε-(γ-Glu)-Lys-isopeptidase activity, which is responsible for isopeptide bond cleavage. METHODS: Venous (jugular vein) and arterial (carotid artery) thrombosis was induced in rats. Rats were intravenously injected with both recombinant destabilase produced in Escherichia coli and a commercial streptokinase preparation. After 24 h, the weight and degree of cross-linking in the thrombi were analysed. Amidolytic activity in rat blood serum was measured in order to evaluate destabilase levels in the blood. RESULTS: Destabilase was definitively shown to cause a 47.6% and 74.6% decrease in the weight of venous and arterial thrombi, respectively. The enzyme proved to be more efficient at dissolving thrombi compared to streptokinase. The combined administration of destabilase and streptokinase has a greater effect than the injection of individual enzymes. Destabilase reduces fibrin stabilization in thrombi. CONCLUSION: Cumulatively, we find that the medicinal leech destabilase is a more efficient thrombolytic agent for dissolving thrombi, which could help increase the overall effectiveness of conventional thrombolytic drugs.

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In rat venous and arterial thrombosis models, intravenous recombinant destabilase, a medicinal leech salivary enzyme, reduced thrombus weight by 47.6% and 74.6% respectively, outperforming streptokinase and showing an even greater combined effect.

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