Tyrosine-Selective Polyfluoroaryl Modification Enables Bioactive Peptides with Enhanced Membrane Permeability and Ligation Capability
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 SNAr with N-terminal cysteines, as confirmed by 19F 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.
Authors
- R Wang
- Quan Zuo (ORCID: https://orcid.org/0000-0002-4451-3380)
- Ximiao Yang
- H Huang
- Xingkai Wang (ORCID: https://orcid.org/0000-0001-6943-9968)
- Quanshu He (ORCID: https://orcid.org/0009-0000-1685-1609)
- Guoqing Li (ORCID: https://orcid.org/0000-0002-2843-6039)
- Z Huang
- J Lu
- Zirui Zhang
- Kuan Hu (ORCID: https://orcid.org/0009-0004-2549-629X)
- Hao Tian
- Jie Yan
Institutions
- Shenyang Pharmaceutical University (CN)
- Target (United States) (US)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
Publication Details
- Journal
- Organic Letters
- Published
- 2026-05-18
- DOI
- https://doi.org/10.1021/acs.orglett.6c01405
- Primary Topic
- Chemical Synthesis and Analysis
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Chinese Academy of Medical Sciences
- Peking Union Medical College
- Beijing Municipal Natural Science Foundation
- Beijing Nova Program
- Fundamental Research Funds for the Central Universities