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Peer-reviewedCC BY 4.0Nature Chemistry

A general strategy towards multicolour fluorogenic peptides for wash-free bioassays

  • Man Sing Wong1,2
  • Lorena Mendive-Tapia1,2
  • Utsa Karmakar1,2
  • Lovelesh Vashist3
  • Zandile Nare4
  • Karolina Tokarczyk4
  • Kohei Iijima5
  • Kazuya Kikuchi5
  • Syed Ali Abbas Abedi3,6
  • Xiaogang Liu3,6
  • Marc Vendrell1,2
6 affiliations
  1. 1Centre for Inflammation Research, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh, UK
  2. 2IRR Chemistry Hub, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh, UK
  3. 3Fluorescence Research Group, Singapore University of Technology and Design, Singapore, Singapore
  4. 4Concept Life Sciences Ltd, Edinburgh Bioquarter, Edinburgh, UK
  5. 5Department of Applied Chemistry, Graduate School of Engineering, The University of Osaka, Suita, Japan
  6. 6School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, Singapore, Singapore
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Abstract

Peptide-based fluorescent probes are valuable tools for live-cell imaging, but conventional labelling approaches often require washing or long incubation, limiting their signal-to-noise ratios. Fluorogenic amino acids (FgAAs) can overcome these limitations, yet their rational design remains challenging owing to the lack of generalizable quenching principles and synthetic routes compatible with diverse fluorophores. Here we developed a general strategy to convert constitutively bright fluorophores into turn-on FgAAs through intramolecular tryptophan-induced quenching. Computational analysis showed that quenching is governed by photoinduced electron transfer or twisted intramolecular charge transfer mechanisms, with adaptability across ultraviolet-to-near-infrared fluorophore scaffolds. We synthesized a large library of multicolour FgAAs and integrated them into solid-phase peptide synthesis to generate turn-on probes for real-time microscopy in live cells. We then designed fluorogenic peptides targeting programmed cell death protein 1 (PD-1), enabling T cell targeted drug screening and identifying avasimibe as a small-molecule modulator of PD-1 activity. This work establishes a rational strategy for designing multicolour FgAAs for peptide engineering, imaging and drug discovery.

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Cite

BibTeXRIS
BibTeX
@article{wong2026general,
  title = {{A general strategy towards multicolour fluorogenic peptides for wash-free bioassays}},
  author = {Man Sing Wong and Lorena Mendive-Tapia and Utsa Karmakar and Lovelesh Vashist and Zandile Nare and Karolina Tokarczyk and Kohei Iijima and Kazuya Kikuchi and Syed Ali Abbas Abedi and Xiaogang Liu and Marc Vendrell},
  journal = {Nature Chemistry},
  year = {2026},
  month = aug,
  doi = {10.1038/s41557-026-02228-0},
  url = {https://doi.org/10.1038/s41557-026-02228-0},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - A general strategy towards multicolour fluorogenic peptides for wash-free bioassays
AU  - Man Sing Wong
AU  - Lorena Mendive-Tapia
AU  - Utsa Karmakar
AU  - Lovelesh Vashist
AU  - Zandile Nare
AU  - Karolina Tokarczyk
AU  - Kohei Iijima
AU  - Kazuya Kikuchi
AU  - Syed Ali Abbas Abedi
AU  - Xiaogang Liu
AU  - Marc Vendrell
PY  - 2026
DA  - 2026/08/26
JO  - Nature Chemistry
DO  - 10.1038/s41557-026-02228-0
UR  - https://doi.org/10.1038/s41557-026-02228-0
AB  - Peptide-based fluorescent probes are valuable tools for live-cell imaging, but conventional labelling approaches often require washing or long incubation, limiting their signal-to-noise ratios. Fluorogenic amino acids (FgAAs) can overcome these limitations, yet their rational design remains challenging owing to the lack of generalizable quenching principles and synthetic routes compatible with diverse fluorophores. Here we developed a general strategy to convert constitutively bright fluorophores into turn-on FgAAs through intramolecular tryptophan-induced quenching. Computational analysis showed that quenching is governed by photoinduced electron transfer or twisted intramolecular charge transfer mechanisms, with adaptability across ultraviolet-to-near-infrared fluorophore scaffolds. We synthesized a large library of multicolour FgAAs and integrated them into solid-phase peptide synthesis to generate turn-on probes for real-time microscopy in live cells. We then designed fluorogenic peptides targeting programmed cell death protein 1 (PD-1), enabling T cell targeted drug screening and identifying avasimibe as a small-molecule modulator of PD-1 activity. This work establishes a rational strategy for designing multicolour FgAAs for peptide engineering, imaging and drug discovery.
SN  - 1755-4330
SN  - 1755-4349
ER  -