title: Synthesis and bioactivity evaluation of dipeptidyl peptidase IV resistant glucagon-like peptide-1 analogues.
abstract: Glucagon-like peptide -1 (GLP-1) is an incretin hormone displaying glucose-dependent stimulation of insulin secretion and trophic effects on the pancreatic β-cells. However, GLP-1 is rapidly degraded to GLP-1(9-36) by dipeptidyl peptidase-IV (DPP-IV), which removes the N-terminal dipeptide His(7)-Ala(8). The rapid inactivation of GLP-1 in the blood circulation limits its clinical application. Hence, we replaced the enzymatic hydrolyzation position Ala(8) with other natural amino acids. The GLP-1 analogues were synthesized rapidly and efficiently under microwave irradiation, using Fmoc/tBu orthogonal protection strategy. Studies on blood-glucose-lowering effect of GLP-1 analogues in vivo were undertaken using 10-week-old male Kunming mice. The metabolic stability was tested by incubation with dipeptidyl peptidase-IV (DPP-IV). Generally, Xaa(8)-GLP-1 analogues exhibit resistance to DPP-IV degradation in vitro and stronger hypoglycemic effect than GLP-1. This may help to understand the structure-activity relationship of GLP-1 analogues.
authors.affiliation: Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Jinpei
authors.initials: J
authors.lastname: Zhou
authors.forename: Shuaijian
authors.initials: S
authors.lastname: Ni
authors.forename: Huibin
authors.initials: H
authors.lastname: Zhang
authors.forename: Hai
authors.initials: H
authors.lastname: Qian
authors.forename: Yushi
authors.initials: Y
authors.lastname: Chi
authors.forename: Wenlong
authors.initials: W
authors.lastname: Huang
authors.forename: Lu
authors.initials: L
authors.lastname: Yu
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Hu
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D004351:Drug Resistance; D004355:Drug Stability; D004734:Energy Metabolism / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D052216:Glucagon-Like Peptide 1