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Aim:A novel hirudin isoform 3 mimetic peptide, named peptide S2, has been prepared by introduction of a stearic acid modification.Results:Peptide S2 exhibited superior inhibitory activity to hirulog-1 (Bivariludin), a peptidomimetic drug used for percutaneous coronary intervention, 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 8 h after administration, and was 10-fold more potent than hirulog-1 300min after administration of 0.1 mol/kg peptide.The enhanced antithrombotic activity could be attributed to its long half-life (T1/2 =212.2 ± 58.4 min), which was 13.1 and 14.7-fold longer than those of hirulog-1(T1/2 =15.1 ± 1.3 min) and peptide 1 (T1/2 =13.5 ± 2.6 min), respectively.Conclusion:Further enzymatic degradation and binding assay with human serum albumin(HAS)demonstrated that the longer duration timeshould be originated from the slowing of trypsin or thrombin-mediated degradation, as well as its binding to HAS.The improved pharmacokinetic properties observed for peptide S2 has made it a promising therapeutic agent for the treatment of thrombi-related diseases.