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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 8 h after administration, and was 10-fold more potent than hirulog-1 300 min after administration of 0.1 μmol/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. 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.
Highlights
Surgical settings showed encouraging results[7,8,9]
We previously found a novel peptidomimetic thrombin inhibitor, named peptide 1 (Table 1), which is derived from the hirudin isoform 3, and it is more potent than hirulog-1 in vitro[15]
Based on the fact that hirudin isoform 3 is more potent than hirudin isoform 1, we previously designed and synthesized a novel hirudin mimetic peptide 1 (Table 1), which contains an anion-binding exosite binding domain (QGDFEPIPEDAYDE), a catalytic active binding domain ((D)-FPRP) and a four Gly linker
Summary
Surgical settings showed encouraging results[7,8,9]. the half-life of hirulog-1 in human plasma is extremely short (T1/2 = 2 0 ~ 25 min), which has dramatically limited the scope of its applications[5]. It is known that modifying peptides with fatty acids can substantially improve their pharmacokinetic properties[10,11], as exemplified by Liraglutide, a peptide drug for the treatment of type 2 diabetes. In this case, a fatty acid is attached to the ε -amino group of Lys[12] of human GLP-1 peptide through a Glu spacer, affording a compound with half-life of 11–5 h13. The inhibitory experiments showed that peptide S2, in which the second Gly residue has been replaced with a modified Lys (stearic acid), exhibited anticoagulant activity comparable to hirulog-1. The much improved anticoagulant activity and pharmacokinetic properties of peptide S2 show promises for the development of peptide S2 as an effective and economic agent for various anticoagulation therapies
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