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

• Published in: Organic process research & development Vol. 28; no. 7; pp. 2896 - 2905
• Main Authors: Ruhl, Kyle E., Di Maso, Michael J., Rose, Harrison B., Schultz, Danielle M., Lévesque, François, Grosser, Shane T., Silverman, Steven M., Li, Shasha, Sciammetta, Nunzio, Mansoor, Umar Faruk
• Format: Journal Article
• Language: English
• Published: American Chemical Society 19-07-2024
• Subjects: data-rich experimentation; solid-phase peptide synthesis; peptide therapeutics; flow chemistry
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.4c00165

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.