title: Formation of cyclic structure at amino-terminus of glucagon-like peptide-1 exhibited a prolonged half-life in vivo.
abstract: The multiple physiological characterizations of glucagon-like peptide-1 (GLP-1) make it a promising drug candidate for the therapy of type 2 diabetes. However, the biological half-life of GLP-1 is short in vivo due to degradation by dipeptidyl peptidase-IV (DPP-IV) and renal clearance. The stabilization of GLP-1 is critical for its utility in drug development. In this study, several GLP-1 mutants containing an N-terminal cyclic conformation were prepared in that the existence of cyclic conformation is predicted to increase the stabilization of GLP-1 in vivo. In this study, the binding capacities of the mutants were determined, the stabilities of the mutants were investigated and the physiological functions of the mutants were compared with those of wild-type GLP-1 in animals. The results indicated that the mutant (GLP1N8) remarkably raised the half-life in vivo; it also showed better glucose tolerance and higher HbA(1c) reduction than GLP-1 and exendin-4 in rodents. These results suggest that the GLP-1 analog (GLP1N8) which contains an N-terminal cyclic structure might be utilized as possible potent anti-diabetic drugs in the treatment of type 2 diabetes mellitus.
authors.affiliation: Department of Pharmacy, Tianjin University of Traditional Medicine, China.
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Cao
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Lida
authors.initials: L
authors.lastname: Tang
authors.forename: Weiren
authors.initials: W
authors.lastname: Xu
authors.forename: Changxiao
authors.initials: C
authors.lastname: Liu
authors.forename: Jianning
authors.initials: J
authors.lastname: Zhang
authors.forename: Min
authors.initials: M
authors.lastname: Gong
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D018819:Dipeptidyl Peptidase 4 / Q000494:pharmacology*; D015195:Drug Design; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000187:drug effects*; D006207:Half-Life; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D008297:Male; D051381:Rats
chemical_list: D001786:Blood Glucose; D018819:Dipeptidyl Peptidase 4; D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents