title: Long-acting GLP-1 analogue in V-shaped conformation by terminal polylysine modifications.
abstract: Glucagon-like peptide-1 (GLP-1) possesses multiple physiological functions, which make it a potential drug candidate for the treatment of type 2 diabetes. However, its clinical application was limited severely by its short half-life in vivo. Therefore, stabilization of GLP-1 is critical for the use of this peptide in drug development. In this study, a novel GLP-1 derivative, VGLP1K6, processed a significantly prolonged half-life in vivo. Structural analysis using molecular dynamics simulations demonstrated that VGLP1K6 has a rigid V-shaped conformation resulting from the intrapeptide disulfide bond. The C-terminal polylysine residues of VGLP1K6 caused the vulnerable N-terminus of GLP-1 (HA-fragment) to reside within the pocket-like cavity of the peptide due to the intrahydrogen bonds. The structural analysis suggested that this structural alteration contributed to the remarkable prolonged half-life of VGLP1K6, which was approximately 70 h. In addition, VGLP1K6 induced better long-acting glucose tolerance and greater HbA1c reductions than GLP-1 in rodents. Our findings suggest that the GLP-1 derivative VGLP1K6 might be a possible potent antidiabetic drug for the treatment of type 2 diabetes mellitus.
authors.affiliation: Department of Pharmacy, Tianjin Traditional Medicine University , Tianjin, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Yang
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Yuli
authors.initials: Y
authors.lastname: Wang
authors.forename: Xuemin
authors.initials: X
authors.lastname: Zheng
authors.forename: Weiling
authors.initials: W
authors.lastname: Kong
authors.forename: Fancui
authors.initials: F
authors.lastname: Meng
authors.forename: Zhixing
authors.initials: Z
authors.lastname: Zhou
authors.forename: Changxiao
authors.initials: C
authors.lastname: Liu
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Min
authors.initials: M
authors.lastname: Gong
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D052216:Glucagon-Like Peptide 1 / Q000737:chemistry* / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000032:analysis; D006207:Half-Life; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D011107:Polylysine / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D018027:Receptors, Glucagon / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D011107:Polylysine; D018027:Receptors, Glucagon; C000593835:Glp1r protein, rat
keywords: GLP-1 analogues; HbA1c; cAMP; glucose tolerance test; insulin stimulation; long-acting GLP-1