Exploring methods for a difficult coupling


*Corresponding authors
Gyros Protein Technologies, Tucson, AZ, USA


With the advancement of peptides into the clinic, the complexity of peptide sequences has continued to increase. With more complex sequences, synthesis difficulties arise, for example, sterically hindered coupling reactions, increased hydrophobicity, among others. Parallel synthesis optimization with induction heating was performed on the Solid Phase Peptide Synthesis (SPPS) of peptides with sterically hindered sequences looking for improvements in crude peptide purity. Several conditions were tested in parallel, including different temperatures, reaction times, and coupling reagents. The crude purity for Aib-ACP was improved from 7.8% using HCTU to 91% by changing to COMU and increasing the reaction temperature to 75 °C using short reaction times.


Peptides are an important tool in drug discovery and development efforts (1at the same time, relatively safe and well tolerated. Consequently, there is an increased interest in peptides in pharmaceutical research and development (R&D). Thus, the rapid discovery and development of peptides is of great interest for the pharma industry. As peptide drug discovery progresses, so does the complexity of peptides and their modifications. Peptide modifications can lead to challenging coupling reactions that require specific conditions such as special solvents, different reaction times, and special handling of the peptides during and after the synthesis in order to achieve optimal purity results (2–5). For this reason, enabling technologies like fast heating methods, real-time UV deprotection monitoring and optimization using parallel conditions have become important.

Parallel synthesis optimization is a useful tool for method development, providing faster results for efficient peptide development. Temperature may be among the parameters explored, with the use of increased temperature protocols (>50 °C) in some cases resulting in shorte ...