title: Stability and bioactivity studies on dipeptidyl peptidase IV resistant glucogan-like peptide-1 analogues.
abstract: Glucagon-like peptide-1 (GLP-1) was once considered as an ideal anti-diabetic candidate for its important role in maintaining glucose homeostasis through the regulation of islet hormone secretion, as well as hepatic and gastric function. However, the major therapeutic obstacle for using native GLP-1 as a therapeutic agent is its very short half-life primarily due to their degradation by the enzyme dipeptidyl peptidase IV (DPP-IV). In this study, GLP-1 analogues with modifications in amino acid site 8, 22 and 23 were synthesized using solid phase peptide synthesis. Resistance of these analogues to DPP-IV cleavage was investigated in vitro by incubation of the peptides with DPP-IV or human plasma. Glucoregulating efficacy of the analogues was evaluated in normal Kunming mice using intraperitoneal glucose tolerance model. Glucose lowering effect of combination therapy (analogue plus Vildagliptin) has also been studied. In vitro studies showed that the modified analogues were much more stable than native GLP-1 (nearly 100% of the peptide keep intact after 4 h incubation). In vivo biological activity evaluation revealed that His8-EEE (the most potent GLP-1 analogues in this study) exhibited significantly improved glycemic control potency (approximately 4.1-fold over saline and 2.5-fold over GLP-1) and longer time of active duration (at least 5 h). Combination therapy also showed the trend of its superiority over mono-therapy. Modified analogues showed increased potency and biological half-time compared with the native GLP-1, which may help to understand the structure-activity relationship of GLP-1 analogues.
authors.affiliation: Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Yinghong
authors.initials: Y
authors.lastname: Zhou
authors.forename: Huibin
authors.initials: H
authors.lastname: Zhang
authors.forename: Hai
authors.initials: H
authors.lastname: Qian
authors.forename: Wenlong
authors.initials: W
authors.lastname: Huang
authors.forename: Baowei
authors.initials: B
authors.lastname: Yang
authors.forename: Jing
authors.initials: J
authors.lastname: Han
authors.forename: Jingpei
authors.initials: J
authors.lastname: Zhou
authors.forename: Yushi
authors.initials: Y
authors.lastname: Chi
authors.forename: Shuaijian
authors.initials: S
authors.lastname: Ni
mesh_terms: D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism* / Q000494:pharmacology; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005951:Glucose Tolerance Test; D006207:Half-Life; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D051379:Mice; D009570:Nitriles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D059748:Proteolysis; D011759:Pyrrolidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D000077597:Vildagliptin
chemical_list: D004338:Drug Combinations; D007004:Hypoglycemic Agents; D009570:Nitriles; D011759:Pyrrolidines; D052216:Glucagon-Like Peptide 1; D018819:Dipeptidyl Peptidase 4; D000077597:Vildagliptin; D000218:Adamantane