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PreprintCC BYChemRxiv

Visible-light-driven C2-phosphonylation of tryptophan in peptides and proteins

  • Ranran Zhu1,2
  • Xiaofei Gao3
  • Xiaoying Lian4,5
  • Diqi Yan4,5
  • Fulai Li1,2
  • Daokuan Sun1,2
  • Ran Zhang1,2
  • Yufen Zhao1,2
  • Yang Wan3
  • Qian Wang4,5
  • Ju WU1,2
5 affiliations
  1. 1Institute of Drug Discovery Technology
  2. 2Ningbo University
  3. 3Key Laboratory of Organic Chemistry, Institute of Organic Chemistry, Jiangxi Science & Technology Normal University
  4. 4Department of Chemistry and Biochemistry
  5. 5University of South Carolina
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Abstract

Tryptophan (Trp) residues are comparatively rare in proteins but are frequently positioned at sites that control folding, molecular recognition, ligand binding, and enzymatic activity. Direct chemical modification of Trp therefore offers a powerful strategy for perturbing protein structure and function. However, methods for installing compact, highly polar functionality onto native Trp residues under mild, protein-compatible conditions remain limited. Here we report a visible-light-driven reductive platform for the C2-selective phosphonylation of Trp-containing peptides and proteins using oxime phosphonates as radical precursors. The reaction proceeds under mild conditions, tolerates diverse peptide sequences containing nearly all proteinogenic amino-acid side chains, and enables late-stage modification of Trp-containing synthetic peptides or peptides derived from structurally complex bioactive molecules. The method further extends to native proteins in aqueous buffer, with LC-MS/MS analysis confirming site-selective modification across a range of protein substrates. Collectively, these results establish photochemical Trp-phosphonylation as a versatile method for peptide diversification, protein conjugation, and chemical control of biomolecular function in situ.

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Cite

BibTeXRIS
BibTeX
@misc{zhu2026visiblelightdriven,
  title = {{Visible-light-driven C2-phosphonylation of tryptophan in peptides and proteins}},
  author = {Ranran Zhu and Xiaofei Gao and Xiaoying Lian and Diqi Yan and Fulai Li and Daokuan Sun and Ran Zhang and Yufen Zhao and Yang Wan and Qian Wang and Ju WU},
  howpublished = {ChemRxiv},
  year = {2026},
  month = sep,
  doi = {10.26434/chemrxiv.15008966/v1},
  url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008966/v1},
  note = {CC BY},
}
RIS
TY  - UNPB
TI  - Visible-light-driven C2-phosphonylation of tryptophan in peptides and proteins
AU  - Ranran Zhu
AU  - Xiaofei Gao
AU  - Xiaoying Lian
AU  - Diqi Yan
AU  - Fulai Li
AU  - Daokuan Sun
AU  - Ran Zhang
AU  - Yufen Zhao
AU  - Yang Wan
AU  - Qian Wang
AU  - Ju WU
PY  - 2026
DA  - 2026/09/17
PB  - ChemRxiv
DO  - 10.26434/chemrxiv.15008966/v1
UR  - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008966/v1
AB  - Tryptophan (Trp) residues are comparatively rare in proteins but are frequently positioned at sites that control folding, molecular recognition, ligand binding, and enzymatic activity. Direct chemical modification of Trp therefore offers a powerful strategy for perturbing protein structure and function. However, methods for installing compact, highly polar functionality onto native Trp residues under mild, protein-compatible conditions remain limited. Here we report a visible-light-driven reductive platform for the C2-selective phosphonylation of Trp-containing peptides and proteins using oxime phosphonates as radical precursors. The reaction proceeds under mild conditions, tolerates diverse peptide sequences containing nearly all proteinogenic amino-acid side chains, and enables late-stage modification of Trp-containing synthetic peptides or peptides derived from structurally complex bioactive molecules. The method further extends to native proteins in aqueous buffer, with LC-MS/MS analysis confirming site-selective modification across a range of protein substrates. Collectively, these results establish photochemical Trp-phosphonylation as a versatile method for peptide diversification, protein conjugation, and chemical control of biomolecular function in situ.
ER  -