Application of Thiol-yne/Thiol-ene Reactions for Peptide and Protein Macrocyclizations

作者：Wang Yuanxiang; Bruno Benjamin J^*; Cornillie Sean; Nogieira Jason M; Chen Diao; Cheatham Thomas E III; Lim Carol S^*; Chou Danny Hung Chieh^*

来源：Chemistry - A European Journal, 2017, 23(29): 7087-7092.

DOI：10.1002/chem.201700572

• peptide macrocyclization
• peptide stapling
• thiol-ene coupling
• thiol-yne coupling

The application of thiol-yne/thiol-ene reactions to synthesize mono-and bicyclic-stapled peptides and proteins is reported. First, a thiol-ene-based peptide-stapling method in aqueous conditions was developed. This method enabled the efficient stapling of recombinantly expressed coil-coiled proteins. The resulting stapled protein demonstrated higher stability in its secondary structure than the unstapled version. Furthermore, a thiol-yne coupling was performed by using an a, w-diyne to react with two cysteine residues to synthesize a stapled peptide with two vinyl sulfide groups. The stapled peptide could further react with another biscysteine peptide to yield a bicyclic stapled peptide with enhanced properties. For example, the cell permeability of a stapled peptide was further increased by appending an oligoarginine cell-penetrating peptide. The robustness and versatility of thiol-yne/thiol-ene reactions that can be applied to both synthetic and expressed peptides and proteins were demonstrated.

• 出版日期2017-5-23