Development of modern continuous flow solid phase peptide synthesis: chemistry, automation and sustainability impact

The invention of solid-phase peptide synthesis (SPPS) in the late 1950s marked the end of the era of laborious and technically difficult classical solution-phase assembly of these biomolecules. SPPS enabled the ready production of defined peptide sequences with unprecedented speed, reliability and scalability, revolutionising both fundamental biochemical research and therapeutic development. Over the following decades, iterative improvements in amino acid protecting group strategies, coupling reagents and instrumentation further cemented SPPS as a foundation of modern peptide science. This mini-review aims to provide a historical overview of the development and application of continuous-flow (CF) methods to SPPS, leading to its present status as the most effective means for the automated, sustainable, chemically efficient production of peptides. By integrating the principles of flow chemistry with solid-phase techniques, CF-SPPS delivers major gains in reagent economy, reaction kinetics and environmental impact. However, a major issue remains with the solid support itself. The continued reliance on resins originally optimised for batch processes and their corresponding unsuitability has restricted the full realisation of CF-SPPS’s potential. Thus, the development and implementation of next-generation polymer supports tailored specifically for CF processes represents a key frontier in the ongoing refinement of CF-SPPS.