(532e) Identifying Diffusional Limitations during Solid Phase Peptide Synthesis in Swollen Polymer Fixed Beds

Solid phase peptide synthesis is a common synthetic chemical approach to polymerize amino acids into a precisely defined sequence to form a peptide. The process, pioneered by Merrifield in the 1960's, uses functionalized swollen polymers to sequentially add one amino acid at a time to the solid phase with periodic deprotection/washing/coupling steps. In recent years, the technology has been looked to for on-demand peptide synthesis as a potential avenue for next generation pharmaceuticals (i.e. personalized medicine). However, the process is either extremely slow or requires substantial excess of reagents and solvents to achieve required purities.
In this work, we demonstrate that the classical chemical process is in fact dominated by internal diffusional limitations, whereby amino acids slowly uptake into the porous resin. The process is further inhibited at late coupling times due to the presence of a more dense frameworks (bound peptides). The work provides heuristics for the intelligent selection of resins and hopes to inspire the next generation of hierarchical materials for solid phase peptide synthesis.