Non-Symmetric Stapling of Tyrosine-Containing Peptides Driven by Intramolecular Non-Covalent Interactions
Year: 2026
Type: preprint
Abstract: Non-symmetric stapling of native peptides that crosslinking two distinct residues is a valuable tool for enriching diversity of peptide macrocycles, yet it is less achieved due to the high demand for chemo- and siteselectivity control, as well as the competitive intermolecular peptide crosslinking. Herein, we reported a noncovalent interaction activation strategy for non-symmetric stapling of tyrosine-containing peptides by employing ethenesulfonyl fluoride (ESF) as a bifunctional crosslinker. Once covalently anchored to peptide, the sulfonyl fluoride motif is activated by non-covalent interactions, which triggers an intramolecular SuFEx click reaction with tyrosine to afford peptide macrocycles. This approach efficiently crosslinks diverse residue pairs, including Cys–Tyr, His–Tyr and Pro–Tyr. Notably, the protocol is scalable and can be performed in solid-phase synthesis, providing a robust access to tyrosine-bridged peptide macrocycles with excellent diversity.
Source: ChemRxiv
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W7222999455