Neoglycolipids for Prolonging the Effects of Peptides: Self-Assembling Glucagon-like Peptide 1 Analogues with Albumin Binding Properties and Potent in Vivo Efficacy

Søren Blok van Witteloostuijn; Karin Margareta Sophia Mannerstedt; Pernille Wismann; Esben Matzen Bech; Mikkel Boas Thygesen; Niels Vrang; Jacob Jelsing; Knud Jørgen Jensen; Søren Ljungberg Pedersen

doi:10.1021/acs.molpharmaceut.6b00787

Neoglycolipids for Prolonging the Effects of Peptides: Self-Assembling Glucagon-like Peptide 1 Analogues with Albumin Binding Properties and Potent in Vivo Efficacy

Søren Blok van Witteloostuijn, Karin Margareta Sophia Mannerstedt, Pernille Wismann, Esben Matzen Bech, Mikkel Boas Thygesen, Niels Vrang, Jacob Jelsing, Knud Jørgen Jensen, Søren Ljungberg Pedersen

Department of Chemistry

17 Citations (Scopus)

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

Original language	English
Journal	Molecular Pharmaceutics
Volume	14
Issue number	1
Pages (from-to)	193-205
Number of pages	13
ISSN	1543-8384
DOIs	https://doi.org/10.1021/acs.molpharmaceut.6b00787
Publication status	Published - 3 Jan 2017

Keywords

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

Access to Document

10.1021/acs.molpharmaceut.6b00787

Cite this

van Witteloostuijn, S. B., Mannerstedt, K. M. S., Wismann, P., Bech, E. M., Thygesen, M. B., Vrang, N., Jelsing, J., Jensen, K. J., & Pedersen, S. L. (2017). Neoglycolipids for Prolonging the Effects of Peptides: Self-Assembling Glucagon-like Peptide 1 Analogues with Albumin Binding Properties and Potent in Vivo Efficacy. Molecular Pharmaceutics, 14(1), 193-205. https://doi.org/10.1021/acs.molpharmaceut.6b00787

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 et al.

In: Molecular Pharmaceutics, Vol. 14, No. 1, 03.01.2017, p. 193-205.

Research output: Contribution to journal › Journal article › Research › peer-review

van Witteloostuijn, SB, Mannerstedt, KMS, Wismann, P, Bech, EM, Thygesen, MB, Vrang, N, Jelsing, J, Jensen, KJ & Pedersen, SL 2017, 'Neoglycolipids for Prolonging the Effects of Peptides: Self-Assembling Glucagon-like Peptide 1 Analogues with Albumin Binding Properties and Potent in Vivo Efficacy', Molecular Pharmaceutics, vol. 14, no. 1, pp. 193-205. https://doi.org/10.1021/acs.molpharmaceut.6b00787

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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",

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