Non-Symmetric Stapling of Tyrosine-Containing Peptides Driven by Intramolecular Non-Covalent Interactions
- 1Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry
- 2Fudan University
- 3Shanghai Engineering Research Center of Industrial Asymmetric Catalysis of Chiral Drugs
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.
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BibTeX
@misc{han2026nonsymmetric,
title = {{Non-Symmetric Stapling of Tyrosine-Containing Peptides Driven by Intramolecular Non-Covalent Interactions}},
author = {Junwei Han and Yi-Chi Lu and Shangli Ding and Qiu-Shuo Zheng and Yu-Qin Wen and Neng-Rong Chen and Chen-Xiao Fu and Longguang Jiang and Fa-Jie Chen and Wan-Zhen Lin and Fen-Er Chen},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15003320/v2},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15003320/v2},
note = {CC BY},
}
RIS
TY - UNPB
TI - Non-Symmetric Stapling of Tyrosine-Containing Peptides Driven by Intramolecular Non-Covalent Interactions
AU - Junwei Han
AU - Yi-Chi Lu
AU - Shangli Ding
AU - Qiu-Shuo Zheng
AU - Yu-Qin Wen
AU - Neng-Rong Chen
AU - Chen-Xiao Fu
AU - Longguang Jiang
AU - Fa-Jie Chen
AU - Wan-Zhen Lin
AU - Fen-Er Chen
PY - 2026
DA - 2026/10/20
PB - ChemRxiv
DO - 10.26434/chemrxiv.15003320/v2
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15003320/v2
AB - 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.
ER -