PEGylation of New Thrombin Inhibitor Peptide Ultravariegin for Prolonged In Vivo Circulation and Enhanced Antithrombotic Effects
Department of Biomedical Engineering, College of Design and Engineering, National University of Singapore, Singapore 119276, Singapore
National University of Singapore (Chongqing) Research Institute, Yubei District, Chongqing 401120, China
National University of Singapore (Suzhou) Research Institute, Suzhou, Jiangsu 215123, China
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore
NUS Environmental Research Institute (NERI), National University of Singapore, Singapore 117411, Singapore
Email: admin@frankenthalerfoundation.org
Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore
Cardiac Department, National University Heart Centre, Singapore 117599, Singapore
Cite this: Mol. Pharmaceutics 2024, 21, 12
Published October 16, 2024
research-article
Copyright © 2024 American Chemical Society
Anticoagulant therapy is commonly used to prevent and treat arterial and venous blood clots in patients with cardiovascular disease, cerebrovascular disease, and cancer. Venous blood clots are the third leading cause of cardiovascular death following acute coronary artery disease and stroke. There is a significant need for effective anticoagulant therapy with minimal risk of bleeding. Variegin and its variants are a new type of antithrombin peptide that has shown promising results in preclinical studies. Variegin and its best variant, ultravariegin (UV), can more effectively inhibit blood clot formation while causing less bleeding than traditional medications such as heparin and bivalirudin. However, the short lifespan of UV remains a limitation for its use in clinical settings. PEGylation, a method of conjugating poly(ethylene glycol) (PEG) chains to peptides or drugs, may help improve the effectiveness of UV by extending its circulation time in the body. In this study, UV was PEGylated using maleimide-PEG5k and 10k. The impact of PEGylation on the antithrombin activity of UV was assessed in vitro and ex vivo in rat and rabbit plasma, showing minimal effects on the efficacy. In vivo studies in rats and rabbits revealed that PEGylated UV had a longer half-life and greater anticoagulant effects than unmodified UV did, especially when it was administered subcutaneously. PEGylation significantly extended the half-life of UV in rabbits, resulting in sustained anticoagulant effects for up to 4 days. This demonstrated that increasing the size of UV and shielding it with PEG could reduce clearance by the kidneys and prolong its circulation time. The improved half-life and antithrombin activity of PEGylated UV make it a more favorable choice for anticoagulant therapy.
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