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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- 作者：Søren B. van Witteloostuijn ; Karin Mannerstedt ; Pernille Wismann ; Esben M. Bech ; Mikkel B. Thygesen ; Niels Vrang ; Jacob Jelsing ; Knud J. JensenSøren L. Pedersen
- 刊名：Molecular Pharmaceutics
- 出版年：2017
- 出版时间：January 3, 2017
- 年：2017
- 卷：14
- 期：1
- 页码：193-205
- 全文大小：570K
- ISSN：1543-8392
文摘
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.