Acylation of Exenatide by Glycolic Acid and its Anti-Diabetic Activities in db/db Mice
To prepare acylated exenatide analogues and investigate their biological properties for guiding the development of PLGA formulations of exenatide.
The acylated exenatide analogues were prepared by reaction with glycolic acid (GA), one constitutional unit of PLGA, and characterized by HPLC-MS/MS and Circular Dichroism (CD). The pharmacokinetic properties and anti-diabetic activities were studied in SD rats and db/db mice, respectively.
Structural characterizations of the acylated products showed that one to four glycolic acids (GAs) were connected to the primary amine groups of exenatide, and there was a conversion of α-helix to β-sheet to some extent. Pharmacokinetic studies in SD rats revealed that acylated exenatides had a similar Tmax with that of the prototype drug, whereas the Cmax and the AUC values of the adducts were significantly decreased. Biological activity tests demonstrated that exenatide and acylated exenatide analogues had similar in vivo antidiabetic activities in terms of controlling blood glucose concentration, HbA1c level, body weight and food intake.
These findings suggest that GA conjugated exenatide had no influence on the peptide efficacy, therefore it’s not necessary to inhibit exenatide acylation in PLGA formulations during the peptide release process.
KEY WORDSacylation anti-diabetic activity exenatide glycolic acid stability
Type 2 diabetes mellitus
Acknowledgments and Disclosures
The authors would like to express thanks to Dr. Dan Donnelly (Programme Leader for Pharmacology, School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds) for his assistance and supply of the helical wheel of exenatide for adaption in this work.
This study was supported by grants from the National Basic Research Program of China (No. 2012CB724003), the National Key Technology Research and Development Program of China (No. 2012BAK25B03) and the National Science and Technology Major Project of the Ministry of Science and Technology of China (No. 2013ZX09402201).
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