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Open AccessArticle

Improved Antithrombotic Activity and Diminished Bleeding Side Effect of a PEGylated αIIbβ3 Antagonist, Disintegrin

1
Department of Medicine, Mackay Medical College, New Taipei City 25245, Taiwan
2
Department of Biochemistry, National Cheng Kung University Medical College, Tainan 70101, Taiwan
3
Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan
*
Authors to whom correspondence should be addressed.
Toxins 2020, 12(7), 426; https://doi.org/10.3390/toxins12070426
Received: 11 May 2020 / Revised: 24 June 2020 / Accepted: 25 June 2020 / Published: 28 June 2020
(This article belongs to the Special Issue Animal Venoms and Their Components: Molecular Mechanisms of Action)
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 dose-dependent 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. PEG-RR: 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.
Keywords: PEGylation; polymer conjugation; disintegrins; stability; protein therapeutics; pharmacokinetic; antiplatelet agent; antithrombotics; safety profiles PEGylation; polymer conjugation; disintegrins; stability; protein therapeutics; pharmacokinetic; antiplatelet agent; antithrombotics; safety profiles
MDPI and ACS Style

Kuo, Y.-J.; Chang, Y.T.; Chung, C.-H.; Chuang, W.-J.; Huang, T.-F. Improved Antithrombotic Activity and Diminished Bleeding Side Effect of a PEGylated αIIbβ3 Antagonist, Disintegrin. Toxins 2020, 12, 426.

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