title: Acylation of exenatide by glycolic acid and its anti-diabetic activities in db/db mice.
abstract: OBJECTIVE
  To prepare acylated exenatide analogues and investigate their biological properties for guiding the development of PLGA formulations of exenatide.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: School of Pharmacy, Yantai University, No. 32 Qingquan Road, 264005, Yantai, Shandong Province, China.
authors.forename: Rongcai
authors.initials: R
authors.lastname: Liang
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.forename: Renyu
authors.initials: R
authors.lastname: Zhang
authors.forename: Yanan
authors.initials: Y
authors.lastname: Shi
authors.forename: Aiping
authors.initials: A
authors.lastname: Wang
authors.forename: Daquan
authors.initials: D
authors.lastname: Chen
authors.forename: Kaoxiang
authors.initials: K
authors.lastname: Sun
authors.forename: Wanhui
authors.initials: W
authors.lastname: Liu
authors.forename: Youxin
authors.initials: Y
authors.lastname: Li
mesh_terms: D000215:Acylation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D000077270:Exenatide; D006016:Glycolates / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D007004:Hypoglycemic Agents / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D014688:Venoms / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D006016:Glycolates; D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; C031149:glycolic acid; D000077270:Exenatide