Tyrosine-Selective Polyfluoroaryl Modification Enables Bioactive Peptides with Enhanced Membrane Permeability and Ligation Capability

Organic Letters 2026

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Authors: Quan Zuo, Guoqing Li, Qichao He, Xingkai Wang, Zirui Zhang, Z Huang, Jie Yan, Hao Tian, H Huang, Ximiao Yang, J Lu, Rui Wang
+1 more Kuan Hu
DOI: 10.1021/acs.orglett.6c01405
Cited by: 1
References: 38

Abstract

We report a tyrosine-selective polyfluoroaryl modification strategy using tetrafluoro-substituted N -methyl luminol reagents. Under mild oxidative conditions, this platform achieves rapid and chemoselective functionalization of Tyr residues across diverse bioactive peptides. The installed tetrafluoroaryl motif serves as a versatile handle for linker-free peptide–peptide ligation via S N Ar with N-terminal cysteines, as confirmed by 19 F NMR and X-ray crystallography. Furthermore, this modification significantly enhances the membrane permeability of cell-penetrating peptides, enabling the cytosolic delivery of macromolecular cargos. This work provides a unified workflow for peptide fluorination, programmable ligation, and physicochemical optimization.

Fields of Study & Subjects

Chemical Synthesis and Analysis RNA Interference and Gene Delivery Supramolecular Self-Assembly in Materials

Publication details

Journal / source
Organic Letters
Publisher
American Chemical Society (ACS)
Volume
28
Issue
21
Pages
6581–6588
Publication date
18 May 2026
Language
EN