title: GLP-1 analogs containing disulfide bond exhibited prolonged half-life in vivo than GLP-1.
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 half-life of GLP-1 is short in vivo due to degradation by dipeptidyl peptidase-IV (DPP-IV) and renal clearance. This indicates that the stabilization of GLP-1 is critical for its utility in drug development. In this study, we developed a cluster of GLP-1 mutants containing an inter-disulfide bond that is predicted to increase the half-life of GLP-1 in vivo. Exendin-4 was also mutated with a disulfide bond similar to the GLP-1 analogs. 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 and exendin-4 in animals. The results indicated that the mutants remarkably raised the half-life in vivo; they also showed better glucose tolerance and higher HbA(1c) reduction than GLP-1 and exendin-4 in rodents. These results suggest that GLP-1 and exendin-4 mutants containing disulfide bonds might be utilized as possible potent anti-diabetic drugs in the treatment of type 2 diabetes mellitus.
authors.affiliation: School of Biosciences, University of Birmingham, UK.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Xuemin
authors.initials: X
authors.lastname: Zheng
authors.forename: Lida
authors.initials: L
authors.lastname: Tang
authors.forename: Weiren
authors.initials: W
authors.lastname: Xu
authors.forename: Min
authors.initials: M
authors.lastname: Gong
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D004220:Disulfides / Q000737:chemistry*; D000077270:Exenatide; D005934:Glucagon / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000627:therapeutic use; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000032:analysis; D006207:Half-Life; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000627:therapeutic use; D007279:Injections, Subcutaneous; D007328:Insulin / Q000097:blood; D008297:Male; D008969:Molecular Sequence Data; D010455:Peptides / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000627:therapeutic use; D011485:Protein Binding; D055550:Protein Stability; D051381:Rats; D014688:Venoms / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000627:therapeutic use
chemical_list: D001786:Blood Glucose; D018819:Dipeptidyl Peptidase 4; D004220:Disulfides; D000077270:Exenatide; D005934:Glucagon; D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D014688:Venoms