Sulfonyl fluoride crosslinker enables nonsymmetric stapling of tyrosine-containing peptides
- Ethenesulfonyl fluoride acts as a two-ended linker that joins two different amino acid side chains within one peptide into a macrocycle.
- Once it attaches to the first residue, local non-covalent interactions activate its sulfonyl fluoride, driving intramolecular SuFEx closure onto tyrosine and limiting intermolecular crosslinking.
- Cys-Tyr, His-Tyr and Pro-Tyr pairings were accessible, and the method scales and works on solid phase.
- A stapled RGD peptide showed strong integrin binding.
💡 Points
Three pairings from one cheap linker is a useful toolkit; tyrosine has been the missing handle in a field dominated by all-hydrocarbon and Cys-based staples. The ESF-derived sulfonyl aryl ether needs a stability check against lactam staples, both hydrolytic and conformational. One RGD example says nothing about αvβ3 versus α5β1 selectivity, so the SAR stays unproven until that panel exists.