title: The fatty acid conjugated exendin-4 analogs for type 2 antidiabetic therapeutics.
abstract: Improved glucagon-like peptide-1 (GLP-1) receptor activation is considered one of the most effective targets for antidiabetic therapy. For this purpose, we modified the GLP-1 analog of exendin-4 using two fatty acids (FA) either lauric acid (LUA, C12) or palmitic acid (PAA, C16) at its two lysine residues, to produce; Lys(12)-FA-Exendin-4 (FA-M2), Lys(27)-FA-Exendin-4 (FA-M1), or Lys(12,27)-diBA-Exendin-4 (FA-Di). The structural, biological, and pharmaceutical characteristics of these exendin-4 analogs were then investigated. Biological activity tests demonstrated that LUA-M1 had well-preserved in vivo antidiabetic activity and in vitro insulinotropic activity with minimum GLP-1 receptor binding affinity loss as compared with exendin-4. Furthermore, pharmacokinetic studies in rats revealed that s.c. administration of LUA-M1 significantly enhanced pharmacokinetic parameters, such as, elimination half-life, mean residence time, and AUC values as compared with exendin-4. The protracted antidiabetic effects of LUA-M1 were also confirmed by prolonged normoglycemia observed in type 2 diabetic mice (20nmol/mouse single injection of exendin-4 or LUA-M1 induced normoglycemia for 6 or 24h, respectively). These findings suggest that FA conjugated exendin-4s should be considered potential candidates for the treatment of diabetes.
authors.affiliation: College of Pharmacy, SungKyunKwan University, 300 Chonchon-dong, Jangan-gu, Suwon 440-746, Korea.
authors.forename: Su Young
authors.initials: SY
authors.lastname: Chae
authors.forename: Yang Gyu
authors.initials: YG
authors.lastname: Choi
authors.forename: Sohee
authors.initials: S
authors.lastname: Son
authors.forename: Sung Youb
authors.initials: SY
authors.lastname: Jung
authors.forename: Doo Sung
authors.initials: DS
authors.lastname: Lee
authors.forename: Kang Choon
authors.initials: KC
authors.lastname: Lee
mesh_terms: D000818:Animals; D000941:Antigens / Q000378:metabolism / Q000627:therapeutic use; D003920:Diabetes Mellitus; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism*; D000077270:Exenatide; D005227:Fatty Acids / Q000627:therapeutic use; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology / Q000627:therapeutic use; D000067757:Glucagon-Like Peptide-1 Receptor; D006207:Half-Life; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D008239:Lysine / Q000378:metabolism / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D019308:Palmitic Acid / Q000627:therapeutic use; D010455:Peptides; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon; D014688:Venoms
chemical_list: D000941:Antigens; D005227:Fatty Acids; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D019308:Palmitic Acid; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D008239:Lysine