title: Synthesis and Evaluation of a Series of Long-Acting Glucagon-Like Peptide-1 (GLP-1) Pentasaccharide Conjugates for the Treatment of Type 2 Diabetes.
abstract: The present study details the development of a family of novel D-Ala(8) glucagon-like peptide-1 (GLP-1) peptide conjugates by site specific conjugation to an antithrombin III (ATIII) binding carrier pentasaccharide through tetraethylene glycol linkers. All conjugates were found to possess potent insulin-releasing activity. Peptides with short linkers (<25 atoms) conjugated at Lys(34) and Lys(37) displayed strong GLP-1 receptor (GLP-1-R) binding affinity. All D-Ala(8) GLP-1 conjugates exhibited prominent glucose-lowering action. Biological activity of the Lys(37) short-linker peptide was evident up to 72 h post-injection. In agreement, the pharmacokinetic profile of this conjugate (t1/2 , 11 h) was superior to that of the GLP-1-R agonist, exenatide. Once-daily injection of the Lys(37) short-linker peptide in ob/ob mice for 21 days significantly decreased food intake and improved HbA1c and glucose tolerance. Islet size was decreased, with no discernible change in islet number. The beneficial effects of the Lys(37) short-linker peptide were similar to or better than either exenatide or liraglutide, another GLP-1-R agonist. In conclusion, GLP-1 peptides conjugated to an ATIII binding carrier pentasaccharide have a substantially prolonged bioactive profile compatible for possible once-weekly treatment of type 2 diabetes in humans.
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, University of Ulster, BT52 1SA Coleraine (UK). n.irwin@ulster.ac.uk.
authors.forename: Nigel
authors.initials: N
authors.lastname: Irwin
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, University of Ulster, BT52 1SA Coleraine (UK).|Diabetes Research Group, School of Health and Life Sciences, Glasgow Caledonian University, Cowcaddens Road, G4 0BA Glasgow (UK).
authors.forename: Steven
authors.initials: S
authors.lastname: Patterson
authors.affiliation: MSD, Kloosterstraat 6, 5349 AB Oss, (The Netherlands).
authors.forename: Martin
authors.initials: M
authors.lastname: de Kort
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, University of Ulster, BT52 1SA Coleraine (UK).
authors.forename: R Charlotte
authors.initials: RC
authors.lastname: Moffett
authors.affiliation: MSD, Kloosterstraat 6, 5349 AB Oss, (The Netherlands).
authors.forename: Jeffry A J
authors.initials: JA
authors.lastname: Wisse
authors.affiliation: MSD, Kloosterstraat 6, 5349 AB Oss, (The Netherlands).
authors.forename: Wim H A
authors.initials: WH
authors.lastname: Dokter
authors.affiliation: MSD, Kloosterstraat 6, 5349 AB Oss, (The Netherlands).
authors.forename: Ebo S
authors.initials: ES
authors.lastname: Bos
authors.affiliation: MSD, Kloosterstraat 6, 5349 AB Oss, (The Netherlands).
authors.forename: André M M
authors.initials: AM
authors.lastname: Miltenburg
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, University of Ulster, BT52 1SA Coleraine (UK).
authors.forename: Peter R
authors.initials: PR
authors.lastname: Flatt
mesh_terms: D000818:Animals; D000990:Antithrombin III / Q000737:chemistry / Q000378:metabolism; D019540:Area Under Curve; D001786:Blood Glucose / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004353:Drug Evaluation, Preclinical; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000737:chemistry* / Q000378:metabolism; 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 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009844:Oligosaccharides / Q000737:chemistry* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D012372:ROC Curve; D018027:Receptors, Glucagon / Q000819:agonists / Q000378:metabolism; D014688:Venoms / Q000737:chemistry / Q000378:metabolism
chemical_list: D000990:Antithrombin III; D001786:Blood Glucose; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D009844:Oligosaccharides; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms
keywords: conjugates; dipeptidyl peptidase IV; glucagon-like peptide-1; glucose homeostasis; insulin; liraglutide