title: Novel fatty chain-modified glucagon-like peptide-1 conjugates with enhanced stability and prolonged in vivo activity.
abstract: A series of fatty chain conjugates of glucagon-like peptide-1(GLP-1) were designed and synthesized. First, eleven cysteine modified peptides (1-11) were prepared using Gly8-GLP-1(7-36)-NH2 peptide as a starting point. Peptides 1, 6, 9, and 11 which showed comparable GLP-1 receptor activate potency and glucose-lowering effect in vivo with Gly8-GLP-1(7-36)-NH2 were selected for second step modifications to yield conjugates 12-23. All conjugates retained significant GLP-1 receptor activate potency and more importantly exerted enhanced albumin-binding properties and in vitro plasma stability. The protracted antidiabetic effects of the most stable compound 14 were further confirmed by both multiple intraperitoneal glucose tolerance test and hypoglycemic efficacies test in vivo. Furthermore, once daily injection of compound 14 to db/db mice achieved long-term beneficial effects on HbA1c lowering and glucose tolerance. Our results suggest that compound 14 is a promising type 2 antidiabetic agent deserving further investigation.
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Han
authors.forename: Xun
authors.initials: X
authors.lastname: Huang
authors.forename: Lidan
authors.initials: L
authors.lastname: Sun
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.forename: Hai
authors.initials: H
authors.lastname: Qian
authors.forename: Wenlong
authors.initials: W
authors.lastname: Huang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002853:Chromatography, Liquid; D052216:Glucagon-Like Peptide 1 / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D057809:HEK293 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D051381:Rats; D017207:Rats, Sprague-Dawley; D017386:Sequence Homology, Amino Acid; D053719:Tandem Mass Spectrometry
chemical_list: D007004:Hypoglycemic Agents; D052216:Glucagon-Like Peptide 1