A novel stearic acid-modified hirudin peptidomimetic with improved pharmacokinetic properties and anticoagulant activity

Abstract

A novel hirudin isoform 3 mimetic peptide, named peptide S2, has been prepared by introduction of a stearic acid modification. Peptide S2 exhibited superior inhibitory activity to hirulog-1 (Bivariludin) and showed significantly higher anticoagulant potency in vivo. Peptide S2 elevated the thrombin time, prothrombin time and activated partial thromboplastin time of rat and human plasma more efficiently than hirulog-1 and the unmodified form of peptide S2 (peptide 1). Furthermore, peptide S2 inhibited arterial thrombosis and inferior vena cava in rat model 8a €‰h after administration, and was 10-fold more potent than hirulog-1 300a €‰min after administration of 0.1a €‰ 1/4mol/kg peptide. The enhanced antithrombotic activity could be attributed to its long half-life (T 1/2 a €‰=a €‰212.2a €‰±a €‰58.4a €‰min), which was 13.1 and 14.7-fold longer than those of hirulog-1 (T 1/2 a €‰=a €‰15.1a €‰±a €‰1.3a €‰min) and peptide 1 (T 1/2 a €‰=a €‰13.5a €‰±a €‰2.6a €‰min), respectively. Further enzymatic degradation and binding assay with human serum albumin (HSA) demonstrated that the longer duration time should be originated from the slowing of trypsin or thrombin-mediated degradation, as well as its binding to HSA. The improved pharmacokinetic properties observed for peptide S2 has made it a promising therapeutic agent for the treatment of thrombi-related diseases.