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Mol Pharm. 2017 Jan 3;14(1):193-205. doi: 10.1021/acs.molpharmaceut.6b00787. Epub 2016 Dec 22.

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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Gubra ApS , Hørsholm Kongevej 11B, 2970 Hørsholm, Denmark.
Department of Chemistry, Faculty of Science, University of Copenhagen , Thorvaldsensvej 40, 1871 Frederiksberg C, Denmark.
Department of Clinical Medicine, Faculty of Health Science, University of Copenhagen , Blegdamsvej 9, 2100 København Ø, Denmark.


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.


biopharmaceutical; glucagon-like peptide 1; glycolipid; half-life extension; lipidation; neoglycolipid; peptide

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