Neoglycolipids for Prolonging the Effects of Peptides: Self-Assembling Glucagon-like Peptide 1 Analogues with Albumin Binding Properties and Potent in Vivo Efficacy.
Søren B van WitteloostuijnKarin MannerstedtPernille WismannEsben M BechMikkel B ThygesenNiels VrangJacob JelsingKnud Jørgen JensenSøren L PedersenPublished in: Molecular pharmaceutics (2016)
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.
Keyphrases
- molecular docking
- high fat diet induced
- type diabetes
- structure activity relationship
- liver failure
- insulin resistance
- drug induced
- metabolic syndrome
- signaling pathway
- binding protein
- blood glucose
- respiratory failure
- physical activity
- dna binding
- adipose tissue
- blood pressure
- intensive care unit
- skeletal muscle
- extracorporeal membrane oxygenation
- mechanical ventilation