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Peer-reviewedCC BY 4.0ACS Central Science

Ninhydrin as a Covalent Warhead for Chemical Proteomic-Enabled Discovery and Selective Engagement of Reactive Arginines

  • Andrew K. Ecker1,2
  • Andreas Langen1
  • Chloe S. Fields1
  • José L. Montaño1
  • Minh Tran1
  • Ian B. Seiple1,2
  • Balyn W. Zaro1
  1. 1University of California, San Francisco , , , ,
  2. 2Scripps Research Institute , , , ,
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Abstract

Covalent molecules have emerged as next-generation therapeutics and as powerful tools for perturbing fundamental biological processes. Chemical proteomic methods to screen for reactive proteinaceous amino acids have transformed small-molecule discovery pipelines, but their application remains mostly limited to sites where reactive cysteines and lysines are present. Here we report a ninhydrin-based warhead that selectively modifies arginine residues, thus expanding the repertoire of amino acids targetable by covalent molecules. Specifically, we developed alkyne-functionalized variants of ninhydrin to establish an arginine-specific chemical proteomics platform, enabling the classification of more than 6,800 unique reactive arginines from one cell line. These studies uncovered potential modification sites on disease-relevant proteins, including reactive arginines within catalytic sites that are essential for function and reactive arginines on proteins lacking reactive cysteines. By endowing a reversible small-molecule binder of cyclophilin A with a ninhydrin warhead, we achieved selective, covalent engagement in cell lysates and attenuation of enzymatic activity in vitro. These findings establish ninhydrin as a warhead for studying arginine reactivity and identifying at scale arginines amenable to covalent modification.

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Cite

BibTeXRIS
BibTeX
@article{ecker2026ninhydrin,
  title = {{Ninhydrin as a Covalent Warhead for Chemical Proteomic-Enabled Discovery and Selective Engagement of Reactive Arginines}},
  author = {Andrew K. Ecker and Andreas Langen and Chloe S. Fields and José L. Montaño and Minh Tran and Ian B. Seiple and Balyn W. Zaro},
  journal = {ACS Central Science},
  year = {2026},
  month = sep,
  doi = {10.1021/acscentsci.6c00922},
  url = {https://pubs.acs.org/acscii/article/12/10/1610/5442588/Ninhydrin-as-a-Covalent-Warhead-for-Chemical},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Ninhydrin as a Covalent Warhead for Chemical Proteomic-Enabled Discovery and Selective Engagement of Reactive Arginines
AU  - Andrew K. Ecker
AU  - Andreas Langen
AU  - Chloe S. Fields
AU  - José L. Montaño
AU  - Minh Tran
AU  - Ian B. Seiple
AU  - Balyn W. Zaro
PY  - 2026
DA  - 2026/09/01
JO  - ACS Central Science
DO  - 10.1021/acscentsci.6c00922
UR  - https://pubs.acs.org/acscii/article/12/10/1610/5442588/Ninhydrin-as-a-Covalent-Warhead-for-Chemical
AB  - Covalent molecules have emerged as next-generation therapeutics and as powerful tools for perturbing fundamental biological processes. Chemical proteomic methods to screen for reactive proteinaceous amino acids have transformed small-molecule discovery pipelines, but their application remains mostly limited to sites where reactive cysteines and lysines are present. Here we report a ninhydrin-based warhead that selectively modifies arginine residues, thus expanding the repertoire of amino acids targetable by covalent molecules. Specifically, we developed alkyne-functionalized variants of ninhydrin to establish an arginine-specific chemical proteomics platform, enabling the classification of more than 6,800 unique reactive arginines from one cell line. These studies uncovered potential modification sites on disease-relevant proteins, including reactive arginines within catalytic sites that are essential for function and reactive arginines on proteins lacking reactive cysteines. By endowing a reversible small-molecule binder of cyclophilin A with a ninhydrin warhead, we achieved selective, covalent engagement in cell lysates and attenuation of enzymatic activity in vitro. These findings establish ninhydrin as a warhead for studying arginine reactivity and identifying at scale arginines amenable to covalent modification.
SN  - 2374-7943
SN  - 2374-7951
ER  -