Enhancement by covalent modification of a helical peptide backbone has been shown to increase the stability of peptide-based therapeutics. We report a new hydrophilic adaptation (staple) that can be used to selectively connect nitrogen, sulfur, and oxygen-based residues, which significantly bolsters the proteolytic stability of peptides. Peptide stapling has been proven successful in a number of biological applications including a mutant WW domain whose stability was increased by 0.74 kcal/mol. Additionally, we have been able to staple an eIF4E cancer inhibitor protein. This new stapling method can also be reversed under mild conditions. We therefore believe that this new method could find numerous biological applications with peptide-based drugs due to its ability to increase the lifetime and effectiveness of the drugs in vivo.

Selective stapling of natural amino acids with a hydrophilic squaric acid-based linker

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.