title: 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 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.
authors.affiliation: Beijing Institute of Biotechnology, Beijing 100071, China.
authors.forename: Zhuguo
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Beijing Institute of Biotechnology, Beijing 100071, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Beijing Institute of Biotechnology, Beijing 100071, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Dalian Medical University, Dalian 116044, Liaoning Province, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Dalian Medical University, Dalian 116044, Liaoning Province, China.
authors.forename: Guozhu
authors.initials: G
authors.lastname: Han
authors.affiliation: Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China.
authors.forename: Xian
authors.initials: X
authors.lastname: Li
authors.affiliation: Beijing Institute of Biotechnology, Beijing 100071, China.
authors.forename: Mingxin
authors.initials: M
authors.lastname: Dong
authors.affiliation: Beijing Institute of Biotechnology, Beijing 100071, China.
authors.forename: Shuo
authors.initials: S
authors.lastname: Yu
authors.affiliation: Beijing Institute of Biotechnology, Beijing 100071, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Beijing Institute of Biotechnology, Beijing 100071, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Hu
authors.affiliation: Beijing Institute of Biotechnology, Beijing 100071, China.
authors.forename: Huiqin
authors.initials: H
authors.lastname: Guo
authors.affiliation: Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China.
authors.forename: Yuanguo
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Dalian Medical University, Dalian 116044, Liaoning Province, China.
authors.forename: Li
authors.initials: L
authors.lastname: Lv
authors.affiliation: Beijing Institute of Biotechnology, Beijing 100071, China.
authors.forename: Qiuyun
authors.initials: Q
authors.lastname: Dai
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects; D001780:Blood Coagulation Tests; D002339:Carotid Arteries / Q000473:pathology; D006629:Hirudins / Q000737:chemistry*; D006801:Humans; D008297:Male; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D057786:Peptidomimetics; D011485:Protein Binding; D051381:Rats; D012709:Serum Albumin / Q000378:metabolism; D013229:Stearic Acids / Q000737:chemistry*; D013917:Thrombin / Q000037:antagonists & inhibitors; D013927:Thrombosis / Q000188:drug therapy / Q000209:etiology; D014682:Vena Cava, Inferior / Q000473:pathology
chemical_list: D000925:Anticoagulants; D006629:Hirudins; D010446:Peptide Fragments; D057786:Peptidomimetics; D012709:Serum Albumin; D013229:Stearic Acids; C031183:stearic acid; D013917:Thrombin