Macrocyclic peptides (the alternate plural tag) covers the same chemistry class as #macrocyclic-peptide. Coverage runs across Circle Pharma's CID-078 in RB1-deficient tumors, Bicycle Therapeutics' bicyclic platform, AI-designed macrocycles for KRAS and beta-catenin, and the academic structural biology behind the field.
The biocatalytic cyclization work — peptide asparaginyl ligase (PAL) platforms, the University of Utah PapB radical-SAM thioether cyclization paper, and the May 7, 2026 Merck Science paper detailing a convergent enzymatic cascade for the oral PCSK9 inhibitor enlicitide decanoate that cuts step count by more than half — has been reducing the cost of macrocyclic series. Stories here cover platform launches, AACR data, and partnership deals.
For the singular form of the tag, see #macrocyclic-peptide. For the broader cyclic class, see #cyclic-peptide.
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 May 2026 Drug Discovery World feature consolidates the case for cyclic peptides as a distinct therapeutic modality: larger and more selective than small molecules, more permeable and cheaper to manufacture than antibodies, and uniquely suited for protein-protein-interaction targets that have resisted traditional drug discovery. The piece traces the recent algorithmic stack — RFDiffusion adaptations for cyclic backbones, AfCycDesign, ProteinMPNN-derived sequence design — alongside the synthesis chemistry advances (one-pot ligations, photo-redox macrocyclizations) that turn computational hits into tractable scaffolds. Over 40 cyclic peptide drugs are now FDA-approved across endocrine, oncology, and antimicrobial uses, and 6+ peptide-drug conjugates sit in Phase 3, per the late-April PDC market analysis.
ScienceDaily on April 27 highlighted a University of Utah Department of Chemistry team's discovery — published in ACS Bio & Med Chem Au — that the radical-SAM enzyme PapB can macrocyclize GLP-1-like peptides in one step by forming a thioether bond between a cysteine thiol and the C-terminal carboxylate, even when the C-terminal residue is D-configured, β-amino-acid-derived, or N-methylated. The chemistry compresses what is normally a multi-step late-stage cyclization into a single enzymatic reaction, materially reducing the cost and complexity of producing oral-bioavailable peptide drugs. The work positions PapB as a platform tool for next-generation incretin and macrocyclic peptide programs.
The American Association for Cancer Research (AACR) Annual Meeting 2026 opens April 17 at the San Diego Convention Center, running through April 22 with 9,500+ sessions, 575 clinical abstracts, 56 clinical trial plenary talks, and 393 late-breaking posters. Multiple peptide biotechs — including Bicycle Therapeutics, Circle Pharma, SignaBlok, and Oncolytics Biotech — are presenting new clinical and preclinical data on macrocyclic peptides, bicyclic peptide drug conjugates, and peptide-based immunotherapies.
The Drug Discovery Chemistry Oral & Macrocyclic Peptides Summit (April 14-15, San Diego) convenes as 66 cyclic peptide drugs have gained global approval and the field races to solve oral bioavailability. Key advances include Chugai's Luna18 achieving 21-47% oral bioavailability and Merck's macrocyclic PCSK9 inhibitor enlicitide delivering injectable-level results in pill form.
Beijing-based Syneron Bio raised $150M in Series B funding with AstraZeneca among investors to develop macrocyclic peptide drugs. The FDA also proposed a new expedited IND pathway.