Anticoagulant Dodecapeptide Suppresses Thrombosis In Vivo by Inhibiting the Thrombin Exosite-I Binding Site.

Abstract

Thrombin is a crucial regulatory serine protease in hemostasis and thrombosis and has been a therapeutic target of thrombotic events. A novel oyster-derived thrombin inhibitory dodecapeptide (IEELEELEAER, P-2-CG) was identified and characterized. P-2-CG prolonged thrombin time from 9.6 s to 23.3 s at 5 mg/mL in vitro. P-2-CG bound to thrombin Exosite-I domain spontaneously. The occupied Exosite-I blocked fibrinogen binding, which prolonged fibrinogen clotting time to 28 s from 18.5 s. Molecule dynamics demonstrated the interaction of P-2-CG and thrombin Exosite-I involved in eight hydrogen bonds and lots of electrostatic forces. The residue Tyr76 at thrombin Exosite-I is one critical amino acid for fibrinogen binding. The Glu11 in P-2-CG was bound with Tyr76 through strong hydrogen bonds and hydrophobic action. P-2-CG also significantly reduced the mortality of mice that suffered an acute pulmonary embolism induced by thrombin and inhibited mice tail thrombosis induced by κ-carrageenan. The thrombin inhibitory efficiency in vitro and antithrombosis in vivo of P-2-CG provided insight for further applications to serve as an antithrombotic agent.

• Authors: Shuzhen Cheng, Yuwei Wang, Hui Chen, Hanxiong Liu, Lishu Wang, Maurizio Battino, Xiaojun Yao, Beiwei Zhu, Ming Du
• Journal: Journal of agricultural and food chemistry (J Agric Food Chem) Vol. 69 Issue 37 Pg. 10920-10931 (Sep 22 2021) ISSN: 1520-5118 [Electronic] United States
• PMID: 34491753 (Publication Type: Journal Article)

Chemical References

• Anticoagulants
• Fibrinogen
• Thrombin

Topics

• Animals
• Anticoagulants
• Binding Sites
• Fibrinogen
• Mice
• Protein Binding
• Thrombin
• Thrombosis (drug therapy, prevention & control)