Macrocyclic Peptides in Drug Discovery

Macrocyclic peptides occupy a unique niche between small molecules and biologics, combining high target affinity with improved metabolic stability. Their conformational constraint reduces entropy loss upon binding, yielding potent and selective modulation of challenging targets such as protein–protein interactions. Advances in cyclisation chemistries, backbone modifications and computational modelling have overcome historical drawbacks of poor cell permeability and limited oral bioavailability. Emerging strategies—ranging from amide N-methylation and ester bond substitution to the incorporation of noncanonical amino acids—permit fine-tuning of physicochemical properties. High-throughput screening platforms, phage-display libraries and in silico design pipelines now generate diverse macrocyclic scaffolds tailored to oncological, infectious and immunological indications. Together, these developments have accelerated the translation of cyclic peptides into clinical candidates and approved therapies, underscoring their global significance as a versatile drug modality.

Research from Nature Portfolio

Recent studies have demonstrated the value of amide-to-ester backbone substitution as an alternative to N-methylation for enhancing membrane permeability. Detailed NMR conformational analysis combined with enhanced sampling molecular dynamics revealed that ester bonds can increase lipophilicity while stabilising membrane-bound states of cyclic hexapeptides. Extending this strategy to cyclic octapeptides and nonapeptides confirmed its broad applicability, offering a rational approach to design membrane-permeable macrocycles with improved cellular uptake and a path towards orally bioavailable leads.

Macrocyclic Peptides in Drug Discovery publication trend

The graph below shows the total number of articles in macrocyclic peptides in drug discovery across all publications each year (not limited to Nature Index journals).

Technical terms

Macrocyclic peptide: A peptide whose N- and C-termini or side chains are covalently linked to form a ring, conferring conformational rigidity and enhanced stability.

Amide-to-ester substitution: Replacement of a backbone amide bond with an ester linkage to reduce hydrogen-bond donors and increase lipophilicity.

N-methylation: Introduction of a methyl group on the backbone amide nitrogen to shield polar groups, improve membrane permeability and protease resistance.

Phage display: A screening technique in which peptide libraries are expressed on the surface of bacteriophages to identify high-affinity binders.

Noncanonical amino acids: Amino acids beyond the 20 standard residues, incorporated via genetic code expansion or chemical synthesis to impart novel functionalities.

Membrane permeability: The ability of a compound to traverse cellular lipid bilayers, often enhanced by intramolecular hydrogen-bonding and lipophilicity balance.

References

1. Diversification of Phage-Displayed Peptide Libraries with Noncanonical Amino Acid Mutagenesis and Chemical Modification. Chemical Reviews (2024).
2. Amide-to-ester substitution as a stable alternative to N-methylation for increasing membrane permeability in cyclic peptides. Nature Communications (2023).
3. Accurate de novo design of membrane-traversing macrocycles. Cell (2022).
4. Macrocycles in Drug DiscoveryLearning from the Past for the Future. Journal of Medicinal Chemistry (2023).