Continuous-Flow Solid-Phase Peptide Synthesis to Enable Rapid, Multigram Deliveries of Peptides

Peptides may revolutionize the treatment of disease by combining the pharmacological benefits found in both large and small molecules into once-daily oral formulations. For decades, batch-mode solid-phase peptide synthesis (SPPS) has been employed throughout peptide drug discovery and development; however, numerous drawbacks have persisted despite advancements in the technology. Herein, we describe a continuous-flow (CF) SPPS workflow to optimize and deliver multigram quantities of peptide fragments, which are easily transformed to macrocyclic or linear peptide APIs. To develop this workflow, we leveraged a 10-amino acid peptide based on a recently disclosed macrocyclic peptide inhibitor of PCSK9. Compared with batch-mode SPPS, CF-SPPS enables rapid, data-rich optimization of peptide sequences with drastic reductions in development efforts, process execution timelines, and waste generation. To meet project demands and deliver multigram quantities, a hydraulically controlled CF-SPPS prototype was developed, which leverages small-scale optimization data to facilitate a seamless transition to larger deliveries of peptides.