Peptide therapeutics are at the forefront of drug development programs for personalized medicine, cancer therapeutics, and metabolic diseases among others. This has driven the search for faster and more efficient solid phase synthesis (SPS) protocols, making method development crucial in the discovery process. Advances in coupling chemistries and the use of increased temperatures (> 60°C) during coupling reactions in combination with automated synthesizers have expanded the SPS toolbox, allowing simultaneous optimization and high-throughput synthesis via parallel synthesis [1-3].
Here we describe the process development and parallel SPS optimization of G-protein coupled receptor targeting peptides. Solid-support and reagent screening are demonstrated using automated peptide synthesis as part of the optimization process for peptides and peptidomimetics. For example, parallel synthesis condition scanning for the fast synthesis of GLP-1 receptor agonists, Pramlintide (H-KCNTATCATQRLANFLVHSSNNFGPILPPTNVGSNTY-NH2) and Lixisenatide (H-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK-NH2), led to an increase of 27% in crude purity for both peptides by changing the resin and the coupling reagent used for the synthesis [4-5]. In the synthesis of sterically hindered Aib-ACP (H-VQ-Aib-Aib-IDYING-NH2) an increase in peptide purity of 30% was observed just by increasing the temperature during synthesis. Coupling reagents, resins and different reaction time combinations for increased crude purity results will be discussed for peptides and peptidomimetic compounds.