Journal
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
Volume 164, Issue -, Pages 105-113Publisher
ELSEVIER
DOI: 10.1016/j.ejpb.2021.04.019
Keywords
Polyglycerol; Site-specific PGylation; Exenatide; PEGylation; PEG; Glucagon-like peptide 1; Diabetes mellitus type II
Categories
Funding
- Deutsche Forschungsgemeinschaft (DFG)
- Bundesministerium fur Bildung und Forschung [13XP5049A]
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Covalent polymer modification of Exenatide can increase its circulation half-life, improve drug efficacy, and Exenatide modified with polymer showed sustained reduction of blood glucose level in diabetic mice.
Exenatide is a small therapeutic peptide being currently used in clinic for the treatment of diabetes mellitus type II, however, displaying a short blood circulation time which makes two daily injections necessary. Covalent polymer modification of a protein is a well-known approach to overcome this limitation, resulting in steric shielding, an increased size and therefore a longer circulation half-life. In this study, we employed site-selective C-terminal polymer ligation of exenatide via copper-catalyzed azide-alkyne-cycloaddition (CuAAC) to yield 1:1conjugates of either poly(ethylene glycol) (PEG) or linear polyglycerol (LPG) of different molecular weights. Our goal was to compare the impact of the two polymers on size, structure and activity of exenatide on the in vitro and in vivo level. Both polymers did not alter the secondary structure of exenatide and expectedly increased its hydrodynamic size, where the LPG-versions of exenatide showed slightly smaller values than their PEG-analogs of same molecular weight. Upon conjugation, GLP-1 receptor activation was diminished, however, still enabled maximum receptor response at slightly higher concentrations. Exenatide modified with a 40 kDa LPG (Ex-40LPG) showed significant reduction of the blood glucose level in diabetic mice for up to 72 h, which was comparable to its PEG-analog, but 9-fold longer than native exenatide (8 h).
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