Bioorthogonal Peptide Macrocyclization Using Oxime Ligation

The biocompatible synthesis of constrained peptides is challenging. Oxime ligation is a bioorthogonal technique frequently used for protein bioconjugation. We report a straightforward method to install N-terminal ketones and aminooxy side chains during standard solid-phase peptide synthesis. Cyclization occurs spontaneously after acidic cleavage or in aqueous buffer. We demonstrate the facile synthesis of protease inhibitors with varying conformational constraint. The most constrained peptide displayed an activity 2 orders of magnitude higher than its linear analog.

Automated summary

The biocompatible synthesis of constrained peptides is achieved by a straightforward method to introduce N-terminal ketones and aminooxy side chains during solid-phase peptide synthesis. Cyclization occurs spontaneously after acidic cleavage or in aqueous buffer. Protease inhibitors with varying conformational constraint are successfully synthesized, and the most constrained peptide exhibits an activity 2 orders of magnitude higher than its linear analog.