title: Neoglycolipids for Prolonging the Effects of Peptides: Self-Assembling Glucagon-like Peptide 1 Analogues with Albumin Binding Properties and Potent in Vivo Efficacy.
abstract: Novel principles for optimizing the properties of peptide-based drugs are needed in order to leverage their full pharmacological potential. We present the design, synthesis, and evaluation of a library of neoglycolipidated glucagon-like peptide 1 (GLP-1) analogues, which are valuable drug candidates for treatment of type 2 diabetes and obesity. Neoglycolipidation of GLP-1 balanced the lipophilicity, directed formation of soluble oligomers, and mediated albumin binding. Moreover, neoglycolipidation did not compromise bioactivity, as in vitro potency of neoglycolipidated GLP-1 analogues was maintained or even improved compared to native GLP-1. This translated into pronounced in vivo efficacy in terms of both decreased acute food intake and improved glucose homeostasis in mice. Thus, we propose neoglycolipidation as a novel, general method for modulating the properties of therapeutic peptides.
authors.affiliation: Gubra ApS , Hørsholm Kongevej 11B, 2970 Hørsholm, Denmark.|Department of Chemistry, Faculty of Science, University of Copenhagen , Thorvaldsensvej 40, 1871 Frederiksberg C, Denmark.
authors.forename: Søren B
authors.initials: SB
authors.lastname: van Witteloostuijn
authors.affiliation: Gubra ApS , Hørsholm Kongevej 11B, 2970 Hørsholm, Denmark.
authors.forename: Karin
authors.initials: K
authors.lastname: Mannerstedt
authors.affiliation: Gubra ApS , Hørsholm Kongevej 11B, 2970 Hørsholm, Denmark.|Department of Clinical Medicine, Faculty of Health Science, University of Copenhagen , Blegdamsvej 9, 2100 København Ø, Denmark.
authors.forename: Pernille
authors.initials: P
authors.lastname: Wismann
authors.affiliation: Gubra ApS , Hørsholm Kongevej 11B, 2970 Hørsholm, Denmark.|Department of Chemistry, Faculty of Science, University of Copenhagen , Thorvaldsensvej 40, 1871 Frederiksberg C, Denmark.
authors.forename: Esben M
authors.initials: EM
authors.lastname: Bech
authors.affiliation: Department of Chemistry, Faculty of Science, University of Copenhagen , Thorvaldsensvej 40, 1871 Frederiksberg C, Denmark.
authors.forename: Mikkel B
authors.initials: MB
authors.lastname: Thygesen
authors.affiliation: Gubra ApS , Hørsholm Kongevej 11B, 2970 Hørsholm, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Vrang
authors.affiliation: Gubra ApS , Hørsholm Kongevej 11B, 2970 Hørsholm, Denmark.
authors.forename: Jacob
authors.initials: J
authors.lastname: Jelsing
authors.affiliation: Department of Chemistry, Faculty of Science, University of Copenhagen , Thorvaldsensvej 40, 1871 Frederiksberg C, Denmark.
authors.forename: Knud J
authors.identifier: 0000-0003-3525-5452
authors.initials: KJ
authors.lastname: Jensen
authors.affiliation: Gubra ApS , Hørsholm Kongevej 11B, 2970 Hørsholm, Denmark.
authors.forename: Søren L
authors.initials: SL
authors.lastname: Pedersen
mesh_terms: D000418:Albumins / Q000378:metabolism*; D000818:Animals; D003692:Delayed-Action Preparations / Q000737:chemistry* / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test / Q000379:methods; D006017:Glycolipids / Q000097:blood*; D006706:Homeostasis / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000737:chemistry; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000418:Albumins; D003692:Delayed-Action Preparations; D006017:Glycolipids; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D052216:Glucagon-Like Peptide 1; D005947:Glucose
keywords: biopharmaceutical; glucagon-like peptide 1; glycolipid; half-life extension; lipidation; neoglycolipid; peptide