Engineering PEG-fatty acid stapled, long-acting peptide agonists for G protein-coupled receptors.

G protein-coupled receptors (GPCRs) play a key role in signal transduction and human pathophysiological processes. Family B GPCRs are activated by a number of secreted peptide hormones, and engineering of these peptide ligands in order to improve stability and half-life, and therefore clinical efficacy has proven successful for drug discovery. In this chapter we discuss a novel peptide engineering strategy that combines peptide side chain stapling with covalent incorporation of a serum protein binding motif in a single step. The application of this approach to the enhancement of the helicity and stability of GLP-1R peptide agonists, resulting in their improved in vitro potencies, in vivo half-lives and ultimately efficacies, will be described. Discussion of the stapling technology and target selection rationale, peptide engineering and final biological characterization of the long-acting agonists will also be provided.