SuFEx based click chemistry for peptide stapling

Click chemistry is a chemical synthesis strategy which relies on covalent assembly of functional building blocks using high‐yielding reactions that are broad in scope, chemoselective, and compatible with water and oxygen. The sulfur (VI) fluoride exchange (SuFEx) is the latest addition to the click family due to the unique stability of the SO 2 F moiety, which confers inertness against acid‐base reactions, resistance to oxidation and reduction, and generally high yields of sulfonylated products. Ethenesulfonyl fluoride (ESF) is a powerful Michael acceptor for installing the SO 2 F group. We are exploring the use of SuFEx chemistry as a powerful tool in peptide stapling, a technique that locks peptide conformation to improve its pharmacological properties. Specifically, we take advantage of a complementary reactivity of two neighboring nucleophilic side chains of a peptide which can undergo a conjugate addition to ESF, followed by fluoride exchange, thus forming a chemical “staple” and locking a specific conformation of the resulting peptide. Such selective modification can inform the development of chemical probes to improve efficacy of a peptide therapeutic, may improve drug delivery, and facilitate the discovery process. Preliminary studies described herein demonstrate feasibility of this approach. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .