Neoglycolipids for Prolonging the Effects of Peptides: Self-Assembling Glucagon-like Peptide 1 Analogues with Albumin Binding Properties and Potent in Vivo Efficacy
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Neoglycolipids for Prolonging the Effects of Peptides : Self-Assembling Glucagon-like Peptide 1 Analogues with Albumin Binding Properties and Potent in Vivo Efficacy. / van Witteloostuijn, Søren Blok; Mannerstedt, Karin Margareta Sophia; Wismann, Pernille; Bech, Esben Matzen; Thygesen, Mikkel Boas; Vrang, Niels; Jelsing, Jacob; Jensen, Knud Jørgen; Pedersen, Søren Ljungberg.
I: Molecular Pharmaceutics, Bind 14, Nr. 1, 2017, s. 193-205.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Neoglycolipids for Prolonging the Effects of Peptides
T2 - Self-Assembling Glucagon-like Peptide 1 Analogues with Albumin Binding Properties and Potent in Vivo Efficacy
AU - van Witteloostuijn, Søren Blok
AU - Mannerstedt, Karin Margareta Sophia
AU - Wismann, Pernille
AU - Bech, Esben Matzen
AU - Thygesen, Mikkel Boas
AU - Vrang, Niels
AU - Jelsing, Jacob
AU - Jensen, Knud Jørgen
AU - Pedersen, Søren Ljungberg
PY - 2017
Y1 - 2017
N2 - 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
AB - 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
KW - neoglycolipid
KW - lipidation
KW - glucagon-like peptide 1
KW - glycolipid
KW - half-life extension
KW - biopharmaceutical
KW - peptide
U2 - 10.1021/acs.molpharmaceut.6b00787
DO - 10.1021/acs.molpharmaceut.6b00787
M3 - Journal article
C2 - 28005376
VL - 14
SP - 193
EP - 205
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
SN - 1543-8384
IS - 1
ER -
ID: 176369858