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Peer-reviewedCC BY 3.0RSC Chemical Biology

Affinity selection mass spectrometry screening discovers new COP1 peptide binders

  • Harsha Negi1,2,3
  • Noor Radhi1
  • Nicolas Schiff2
  • Sam A. Jamieson4
  • Deanna Shea5
  • Martin Middleditch5
  • Robert Mullin2
  • Renata Kowalczyk2,3
  • Paul W. Harris2,3
  • Peter D. Mace4,3
  • Daniel Conole1,3
5 affiliations
  1. 1Department of Cancer Sciences, Faculty of Medical and Health Sciences, University of Auckland 85 Park Rd, Grafton Auckland 1023 New Zealand
  2. 2School of Biological Sciences, University of Auckland 23 Symonds St Auckland 1010 New Zealand
  3. 3Maurice Wikins Centre for Molecular Biodiscovery, University of Auckland Auckland 1142 New Zealand
  4. 4Department of Biochemistry, University of Otago 710 Cumberland St Dunedin 9016 New Zealand
  5. 5Mass Spectrometry Hub, School of Biological Sciences, University of Auckland 23 Symonds St Auckland 1010 New Zealand
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Abstract

Targeting E3 ubiquitin ligases with chemical probes remains a major challenge, despite their central roles in cellular regulation and disease. Constitutive photomorphogenic 1 (COP1) is an E3 ligase whose complex, adaptor-dependent biology has made its selective targeting difficult. Here, we develop a peptide-based affinity selection mass spectrometry (Pep-AS-MS) platform to discover new peptide based COP1 binders. Leveraging a mass spectrometry compatible library design, fluorescence-guided selection optimisation, and an open-source software driven target-decoy database strategy for peptide identification and quantification, we enable hit ranking from highly complex combinatorial libraries. Using this approach, we identify and validate six previously unreported COP1-binding peptides, including ligands with binding potencies comparable to the native TRIB1 motif. This work establishes a quantitative and accessible Pep-AS-MS framework for ligand discovery against challenging protein–protein interaction targets and provides new chemical tools to interrogate COP1 biology.

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Cite

BibTeXRIS
BibTeX
@article{negi2026affinity,
  title = {{Affinity selection mass spectrometry screening discovers new COP1 peptide binders}},
  author = {Harsha Negi and Noor Radhi and Nicolas Schiff and Sam A. Jamieson and Deanna Shea and Martin Middleditch and Robert Mullin and Renata Kowalczyk and Paul W. Harris and Peter D. Mace and Daniel Conole},
  journal = {RSC Chemical Biology},
  year = {2026},
  month = sep,
  doi = {10.1039/d6cb00250a},
  url = {https://doi.org/10.1039/d6cb00250a},
  note = {CC BY 3.0},
}
RIS
TY  - JOUR
TI  - Affinity selection mass spectrometry screening discovers new COP1 peptide binders
AU  - Harsha Negi
AU  - Noor Radhi
AU  - Nicolas Schiff
AU  - Sam A. Jamieson
AU  - Deanna Shea
AU  - Martin Middleditch
AU  - Robert Mullin
AU  - Renata Kowalczyk
AU  - Paul W. Harris
AU  - Peter D. Mace
AU  - Daniel Conole
PY  - 2026
DA  - 2026/09/10
JO  - RSC Chemical Biology
DO  - 10.1039/d6cb00250a
UR  - https://doi.org/10.1039/d6cb00250a
AB  - Targeting E3 ubiquitin ligases with chemical probes remains a major challenge, despite their central roles in cellular regulation and disease. Constitutive photomorphogenic 1 (COP1) is an E3 ligase whose complex, adaptor-dependent biology has made its selective targeting difficult. Here, we develop a peptide-based affinity selection mass spectrometry (Pep-AS-MS) platform to discover new peptide based COP1 binders. Leveraging a mass spectrometry compatible library design, fluorescence-guided selection optimisation, and an open-source software driven target-decoy database strategy for peptide identification and quantification, we enable hit ranking from highly complex combinatorial libraries. Using this approach, we identify and validate six previously unreported COP1-binding peptides, including ligands with binding potencies comparable to the native TRIB1 motif. This work establishes a quantitative and accessible Pep-AS-MS framework for ligand discovery against challenging protein–protein interaction targets and provides new chemical tools to interrogate COP1 biology.
SN  - 2633-0679
ER  -