Science Perspective (May 8): Pelletier Frames Merck Enlicitide Biocatalytic Cascade as a Template for the Entire Oral Macrocyclic Peptide Modality
Joelle Pelletier's perspective in Science (volume 392, pages 582-583, published online May 8) accompanies the Merck enlicitide biocatalytic synthesis paper and frames the enzyme-cascade route — engineered enzymes plus chromatography-free crystallization to cut step count by more than half — as a template that goes well beyond enlicitide. The piece argues that the limiting step for oral macrocyclic peptide therapeutics has been the manufacturing cost of multi-step protected-residue chemistry, not pharmacology or pharmacokinetics; biocatalysis collapses the cost curve and unlocks a pipeline of oral peptides at large molecular weights that have been quietly stuck in preclinical or Phase 1 economics. The framing matters as enlicitide (oral PCSK9 inhibitor with 57% LDL-C reduction at 24 weeks) heads toward NDA filing.