Construction and functional evaluation of hirudin derivatives with low bleeding risk.
The purpose of this study was to design and evaluate hirudin (HIR) derivatives with low bleeding risk. In these derivatives, the factor (F) XIa, FXa, and thrombin recognition peptides (EPR, GVYAR, and LGPR, respectively) were linked to the N-terminus of HIR. The intact derivatives have no anticoagulant activity because of the extension of the N-terminus of HIR. After cleavage by the corresponding coagulation factor that occurs on the activation of the coagulation system and in the presence of the thrombus, its activity is released. This limited the anticoagulant activity of these derivatives to the vicinity of the thrombus, and as a result, systemic bleeding complications were avoided. The definite antithrombotic effect and low bleeding parameters of these derivatives were investigated in rat carotid artery and inferior vena cava thrombosis models. In both models, the three derivatives showed significant antithrombotic effects, indicating that anticoagulant activity could be successfully released in vivo. Moreover, the bleeding parameters of these derivatives were lower than that of HIR as indicated by the values of activated partial thromboplastin time (APTT) and thrombin time (TT). To further assess the safety of these derivatives, bleeding time was measured in a mouse tail-cut model. Although the derivatives had obvious effects on bleeding at a dose of 6 mg/kg, the effect of these derivatives on bleeding was significantly weaker than that of HIR at a dose of 1.5 mg/kg. Thus, the benefit-to-risk profiles of the derivatives were superior to that of HIR.
Zhang
Chuanling
C
Key Lab of Experimental Hematology, Beijing Institute of Radiation Medicine, 27 Taiping Road, Beijing, P. R. China.
Yu
Aiping
A
Yuan
Bin
B
Dong
Chunna
C
Yu
Hongyang
H
Wang
Lisheng
L
Wu
Chutse
C
D000818:Animals; D000925:Anticoagulants / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects*; D003001:Cloning, Molecular; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005343:Fibrinolytic Agents / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D006470:Hemorrhage / Q000139:chemically induced*; D006629:Hirudins / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D010314:Partial Thromboplastin Time; D011355:Prodrugs / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D018570:Risk Assessment; D013918:Thrombin Time; D013927:Thrombosis / Q000097:blood / Q000517:prevention & control*; D020246:Venous Thrombosis / Q000097:blood / Q000517:prevention & control
D000925:Anticoagulants; D005343:Fibrinolytic Agents; D006629:Hirudins; D011355:Prodrugs; D011993:Recombinant Fusion Proteins