Beyond the Canonical 20: Peptide Discovery with Non-Canonical Amino Acids

Amino acids are central to biology as signaling molecules and as the building blocks of peptides and proteins, which represent an expanding class of drugs with vast therapeutic potential. The precise modulation of individual residues in therapeutic peptides and proteins is crucial to enhance their pharmacological properties. Expanding beyond the twenty proteinogenic amino acids to include non-canonical amino acids (ncAAs) offers powerful strategies to optimize the stability, selectivity, and potency of peptides. Including ncAAs in the early discovery phase can significantly accelerate lead development and clinical translation. This review examines how diverse platforms integrate ncAAs in early discovery and compares the capabilities and limitations of these discovery technologies. Finally, key challenges are outlined that must be addressed to drive future innovations and explore new therapeutic avenues. Together, these approaches mark a shift towards peptide drug discovery where non-canonical chemistry is not an exception but a necessity.