Stability, binding

Retatrutide, Eli Lilly's first-in-class GLP-1/GIP/glucagon triple agonist, demonstrates what non-canonical amino acids can achieve at clinical scale. In Phase 3 trials, patients lost up to 28.7% body weight over 68 weeks, with improvements in osteoarthritis pain and physical function.

Two ncAAs are central to the drug's performance. Aib (alpha-aminoisobutyric acid) at positions 2 and 20 locks the peptide into helical geometry and confers resistance to DPP-4 proteases, the enzymes that rapidly degrade natural GLP-1 in the body. Alpha-methyl-L-leucine at position 13 strengthens hydrophobic contacts with receptor binding surfaces. Together with a C20 fatty diacid for albumin binding, these modifications transform a 39-residue peptide from a rapidly cleared signalling molecule into a once-weekly therapeutic (Eli Lilly, 2025).

Retatrutide illustrates the commercial reality: ncAAs are already in blockbuster drugs. The question for peptide developers is not whether ncAAs add value, but how many can be incorporated and at what manufacturing scale.