We recently discovered a facile transformation that occurs between perfluoroaromatic molecules and a cysteine thiolate, which can be arylated at room temperature. This new approach enabled us further to selectively modify cysteine residues in unprotected peptides. This presentation will focus on the developed applications for the perfluoroaryl-cysteine conjugation chemistry in the area of peptide �stapling�. The newly devised stapling approach provides a unique access to peptide variants containing rigid perfluoroaromatic bridging motifs. The stapling modification performed on a peptide sequence designed to bind the C-terminal domain of an HIV-1 capsid assembly polyprotein (C-CA), showed enhancement in binding, cell permeability, and proteolytic stability properties, as compared to the unstapled analog. Furthermore, we will demonstrate how the chemical stability of the formed staples allowed us to use this motif in the native chemical ligation mediated synthesis of a small protein affibody that is capable of binding the Human Epidermal Growth Factor 2 (HER-2) receptor. Lastly, recent developments enabling us to conduct this chemistry in water will be highlighted.

Peptide stapling enabled by cysteine perfluoroarylation

246th National Meeting (2013)

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