A novel stearic acid-modified hirudin peptidomimetic with improved pharmacokinetic properties and anticoagulant activity
| Autor: | Mingxin Dong, Yuanyuan Huang, Zhuguo Liu, Xian Li, Yu Wang, Yan Zhang, Jie Hu, Qiuyun Dai, Guozhu Han, Li Lv, Shuo Yu, Yuanguo Cheng, Zheng Yu, Huiqin Guo |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Male
Peptidomimetic Serum albumin Hirudin Peptide Vena Cava Inferior Thrombin time Inferior vena cava Article medicine Animals Humans Blood Coagulation Serum Albumin chemistry.chemical_classification Multidisciplinary biology medicine.diagnostic_test Chemistry Thrombin Anticoagulants Thrombosis Hirudins Human serum albumin Trypsin Peptide Fragments Rats Carotid Arteries medicine.vein Biochemistry biology.protein Blood Coagulation Tests Peptidomimetics Stearic Acids medicine.drug Protein Binding |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|