Programmable amide bond formation using de novo ligases

De novo amide ligases with a cysteine catalytic triad can be computationally programmed to form selective amide bonds across diverse substrate classes, outcompeting hydrolysis.

• Why it matters: Conventional amide synthesis often needs stoichiometric coupling agents and protecting-group steps, while natural enzymes are limited by narrow substrate scope and costly engineering.
• What they did: The team designed complementary peptide ligases to functionalize either a polypeptide N-terminus or a single lysine among 36 competing lysines, validating designs with crystal structures and modeling. They also designed stereoselective ligases for a key amide-bond step in lenacapavir synthesis.
• The result: Structural and modeling results suggest amidation is favored because catalytically competent geometry forms upon acceptor binding, enabling programmable, selective amide formation for both polypeptides and small bioactive molecules.

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