Quinoline heterocycles

Quinoline heterocycles appear in numerous approved small-molecule drugs but have been absent from ribosomally produced peptides. Non-canonical amino acids bridge this gap by introducing small-molecule pharmacophores directly into genetically encoded peptide sequences.

By incorporating beta-keto and gamma-keto ncAAs at the N-terminus of ribosomal peptides, researchers enabled an intramolecular Friedlander reaction that builds quinoline rings directly within the peptide backbone. The quinoline itself serves as the macrocyclisation element, creating a hybrid molecule with both peptide and small-molecule character (Knudson et al., 2026).

This opens peptide libraries to chemical space previously exclusive to synthetic chemistry. Ribosomal display libraries up to trillion-member scale can, in principle, be designed with embedded drug-like heterocycles, combining the target selectivity of peptides with the pharmacological properties of small molecules. For drug discovery, it means screening larger chemical space faster, and for manufacturing, ribosomally produced peptides avoid the step-count limitations of total chemical synthesis.