title: A novel GLP-1 analog exhibits potent utility in the treatment of type 2 diabetes with an extended half-life and efficient glucose clearance 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 half-life of GLP-1 is short in vivo due to degradation by dipeptidyl peptidase-IV (DPP-IV) and renal clearance. Therefore, the stabilization of GLP-1 is critical for its utility in drug development. Based on our previous research, a GLP-1 analog that contained an intra-disulfide bond exhibited a prolonged biological half-life. In this study, we improved upon previous analogs with a novel GLP-1 analog that contained a tryptophan cage-like sequence for an improved binding affinity to the GLP-1 receptor. The binding capacities and the stabilities of GLP715a were investigated, and the physiological functions of the GLP715a were compared to those of the wild-type GLP-1 in animals. The results demonstrated that the new GLP-1 analog (GLP715a) increased its biological half-life to approximately 48h in vivo; GLP715a also exhibited a higher binding affinity to the GLP-1 receptor than the wild-type GLP-1. The increased binding capacity of GLP715a to its receptor resulted in a quick response to glucose administration. The long-acting anti-diabetic property of GLP715a was revealed by its increased glucose tolerance, higher HbA(1c) reduction, more efficient glucose clearance and quicker insulin stimulation upon glucose administration compared to the wild-type GLP-1 in rodents. The improved physiological characterizations of GLP715a make it a possible potent anti-diabetic drug in the treatment of type 2 diabetes mellitus.
authors.affiliation: School of Bioscience, University of Birmingham, UK.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Weiren
authors.initials: W
authors.lastname: Xu
authors.forename: Lida
authors.initials: L
authors.lastname: Tang
authors.forename: Min
authors.initials: M
authors.lastname: Gong
authors.forename: Jianning
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose / Q000032:analysis*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D015195:Drug Design; D004355:Drug Stability; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use; D000067757:Glucagon-Like Peptide-1 Receptor; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000032:analysis; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use; D007328:Insulin / Q000097:blood*; D007700:Kinetics; D008297:Male; D008969:Molecular Sequence Data; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D018027:Receptors, Glucagon / Q000378:metabolism*; D044967:Serum / Q000737:chemistry / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014364:Tryptophan / Q000737:chemistry / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D018819:Dipeptidyl Peptidase 4; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D018027:Receptors, Glucagon; D014364:Tryptophan; C000593833:GLP1R protein, human; C000593835:Glp1r protein, rat