Improved antithrombotic activity and diminished bleeding side effect of a PEGylated alphaIIb beta 3 antagonist, disintegrin
Journal
Toxins
Journal Volume
12
Journal Issue
7
Pages
426
Date Issued
2020
Author(s)
Abstract
Polymer polyethylene glycol (PEG), or PEGylation of polypeptides improves protein drug stability by decrease degradation and reduces renal clearance. To produce a pharmaceutical disintegrin derivative, the N-terminal PEGylation technique was used to modify the disintegrin derivative [KGDRR]trimucrin for favorable safety and pharmacokinetic profiles and antithrombotic efficacy. We compared intact [KGDRR]trimucrin (RR) and PEGylated KGDRR (PEG-RR) by in vitro and in vivo systems for their antithrombotic activities. The activity of platelet aggregation inhibition and the bleeding tendency side effect were also investigated. PEG-RR exhibited optimal potency in inhibiting platelet aggregation of human/mouse platelet-rich plasma activated by collagen or ADP with a lower IC50 than the intact derivative RR. In the illumination-induced mesenteric venous thrombosis model, RR and PEG-RR efficaciously prevented occlusive thrombosis in a dosedependent manner. In rotational thromboelastometry assay, there was no effect of PEG-RR in human whole blood coagulation even given at a higher concentration (30 μg/mL), while RR slightly prolonged clotting time. However, RR and PEG-RR were not associated with severe thrombocytopenia or bleeding in FcγRIIa-transgenic mice at equally efficacious antithrombotic dosages. We also found the in vivo half-life of PEGylation was longer than RR (RR: 15.65 h vs. PEGRR: 20.45 h). In conclusion, injectable PEG-RR with prolonged half-life and decreased bleeding risk is a safer anti-thrombotic agent for long-acting treatment of thrombus diseases. ? 2020 by the authors.
Subjects
Antiplatelet Agent; Antithrombotics; Disintegrins; PEGylation; Pharmacokinetic; Polymer Conjugation; Protein Therapeutics; Safety Profiles; Stability
SDGs
Other Subjects
disintegrin; eptifibatide; fibrinogen receptor antagonist; trimucrin; unclassified drug; antithrombocytic agent; disintegrin; Fc receptor; Fc receptor IIa; fibrinogen receptor; fibrinolytic agent; macrogol; peptide; trimucrin; animal cell; animal model; animal tissue; antithrombotic activity; Article; bleeding; bleeding tendency; blood clotting parameters; blood clotting time; clot firmness; controlled study; experimental thrombosis; half life time; high performance liquid chromatography; human; human cell; IC50; male; mass spectrometry; maximum clot; mouse; nonhuman; PEGylation; polyacrylamide gel electrophoresis; protein modification; tail bleeding time; thrombocyte aggregation inhibition; thrombocytopenia; thromboelastometry; thrombosis; turbidimetry; venule; animal; bleeding; blood; blood clotting; chemistry; comparative study; disease model; drug effect; drug formulation; genetics; Institute for Cancer Research mouse; metabolism; thrombocyte aggregation; thrombosis; transgenic mouse; Animals; Blood Coagulation; Disease Models, Animal; Disintegrins; Drug Compounding; Fibrinolytic Agents; Hemorrhage; Humans; Male; Mice; Mice, Inbred ICR; Mice, Transgenic; Peptides; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Polyethylene Glycols; Receptors, IgG; Thrombocytopenia; Thrombosis
Type
journal article