Science (May 7): Merck Publishes Biocatalytic Cascade Route to Enlicitide Decanoate, the Investigational Oral PCSK9 Inhibitor
Merck scientists published in Science a convergent biocatalytic synthesis of enlicitide decanoate, an investigational oral PCSK9 inhibitor and macrocyclic peptide. A tailored suite of engineered enzymes catalyzes selective peptide fragment formation, coupling, and macrocyclization in a protecting-group-free sequence; combined with chromatography-free crystallizations, the route reduces step count by more than half versus prior state-of-the-art methods. Enlicitide is in Phase 3 (CORALreef, with –55.8% LDL-C reported earlier in 2026) and would be the first oral PCSK9 inhibitor if approved. The paper matters beyond enlicitide: protein-engineering-led cascades shift the cost basis for any large macrocyclic peptide program facing peptide-CDMO bottlenecks.