Interest in macrocyclic peptides (MCPs) continues to grow, which means manufacturers are facing mounting pressure to develop production methods capable of supporting commercial-scale demand of these molecules. While they offer a unique combination of potency, selectivity, and drug-like properties, the structural complexity of MCPs has historically made them difficult and costly to manufacture using traditional peptide synthesis techniques. As a result, new manufacturing approaches are emerging that aim to improve efficiency, scalability, and sustainability while expanding access to this promising class of therapeutics.

In this episode of Off Script, we spoke with David Thaisrivongs, executive director, head of biocatalysis at Merck, about research recently published in Science detailing a biocatalytic manufacturing process for enlicitide, an investigational oral macrocyclic peptide designed to lower LDL cholesterol. The conversation explores the limitations of conventional solid-phase peptide synthesis, how Merck leveraged enzyme-driven manufacturing and crystallization strategies to significantly reduce process complexity, and why minimizing chromatography can be critical for commercial-scale peptide production. He also discussed the broader implications of biocatalysis for manufacturing increasingly complex therapeutic modalities and how the technology could help shape the future of pharmaceutical production.