Biocatalysis has emerged as the most consequential chemistry shift behind oral macrocyclic peptide therapeutics. Engineered enzymes that catalyze selective fragment formation, coupling, and macrocyclization without protecting groups are replacing the multi-step protected-residue chemistry that has kept many oral peptide candidates stuck in preclinical or Phase 1 economics.
Covered here: Merck's May 7, 2026 Science paper describing a convergent biocatalytic cascade for enlicitide decanoate — the oral PCSK9 inhibitor in Phase 3 CORALreef — that cuts step count by more than half versus prior chemistry; Joelle Pelletier's accompanying May 8 Science Perspective framing the cascade as a template for the entire oral macrocyclic peptide modality; the University of Utah PapB radical-SAM enzyme paper showing one-step thioether cyclization of GLP-1-like peptides; and the broader peptide asparaginyl ligase (PAL) platform work running through Bicycle Therapeutics and academic structural biology labs.
Stories here cover platform announcements, peer-reviewed mechanism papers, and the cost-curve implications for oral peptide pipelines. See #macrocyclic-peptides, #oral-peptide, and #enlicitide.
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.
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.
A Nature Communications paper published April 27 mined natural diversity in Viola plants to discover 29 new peptide asparaginyl ligases (PALs) — enzymes that catalyze cyclization of synthetic peptide chains. The work characterizes a pH-dependent cyclization mechanism and defines transferable expression-increasing principles, substantially expanding the enzymatic toolkit available for cyclic peptide drug development. The discovery is timely given the surge of macrocyclic peptide programs at Circle Pharma, Bicycle Therapeutics, and Unnatural Products.