Journal Article

Recombinant Expression and Stapling of a Novel Long-Acting GLP-1R Peptide Agonist

Zou, Huafei, Amso, Zaid, Lear, Sam, Huang, David, Nguyen-Tran, Vân T. B., Shen, Weijun, Lee, Candy, Lei, Lei, Zhou, Zhihong, Seo, Hyosuk

2020

Overview

Owing to their pleiotropic metabolic benefits, glucagon-like peptide-1 receptor (GLP-1R) agonists have been successfully utilized for treating metabolic diseases, such as type 2 diabetes and obesity. As part of our efforts in developing long-acting peptide therapeutics, we have previously reported a peptide engineering strategy that combines peptide side chain stapling with covalent integration of a serum protein-binding motif in a single step. Herein, we have used this strategy to develop a second generation extendin-4 analog rigidified with a symmetrical staple, which exhibits an excellent in vivo efficacy in an animal model of diabetes and obesity. To simplify the scale-up manufacturing of the lead GLP-1R agonist, a semisynthesis protocol was successfully developed, which involves recombinant expression of the linear peptide followed by attachment of a polyethylene glycol (PEG)-fatty acid staple in a subsequent chemical reaction step.

• Publisher: MDPI,MDPI AG
• Subject: Animals / diabetes / Diabetes Mellitus, Type 2 / Exenatide - analogs & derivatives / Exenatide - chemistry / Exenatide - metabolism / Fatty Acids - chemistry / Glucagon-Like Peptide-1 Receptor - agonists / Glucagon-Like Peptide-1 Receptor - metabolism / lipidation / Male / Mice / Molecular Structure / Obesity / Peptides - chemistry / Peptides - metabolism / Polyethylene Glycols - chemistry / recombinant expression / semisynthesis / stapled peptide