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 - 2017/1/3
Y1 - 2017/1/3
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
SN - 1543-8384
VL - 14
SP - 193
EP - 205
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
IS - 1
ER -