Perfluoroarene-based Peptide Macrocycles

Perfluoroarene-based Peptide Macrocycles

There are many methods to modify cysteine, which include alkylation, conjugate addition, oxidation, and reduction.

Recently, it was found that it is possible to arylate cysteine in the context of bioconjugation using sufficiently activated reagents. The cysteine perfluoroarylation can be used for mild functionalization of cysteine thiolate moieties.

This is a new and mild synthetic platform for cysteine arylation. The developed method operates at room temperature in polar organic solvents and shows excellent selectivity and functional group tolerance. As a result, one can utilize this approach towards stapling unprotected peptides, thereby positively altering their biological properties. It was demonstrated incorporation of a perfluoroaryl staple within the small tri-helical affibody protein.

Perfluoroarene-based peptide macrocycle is a stapling modification performed on a peptide sequence showed enhancement in binding, cell permeability, and proteolytic stability properties, as compared to the unstapled analog.

It was found that the utility of peptide macrocyclization through perfluoroaryl-cysteine chemistry to improve the ability of peptides to cross the blood−brain barrier. Multiple macrocyclic analogues of the peptide transportan-10 were investigated that displayed increased uptake in two different cell lines and improved proteolytic stability. The abiotic peptide macrocycles can exhibit significantly enhanced penetration of the brain.