ReDisulphID: A discovery platform for thiol redox sensors identifies a druggable site regulating p53 activation

  • Redox Biol. 2026 Jul:94:104196. doi: 10.1016/j.redox.2026.104196.
Pierre Coleman  1 ,  Anna Laddach  2 ,  Rhys Anderson  3 ,  Xiaoping Yang  4 ,  Ravi Kumar  5 ,  Ajay Shah  5 ,  Franca Fraternali  6 ,  Joseph R Burgoyne  7
Affiliations
  • 1. School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, The British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas' Hospital, London, SE1 7EH, UK. Electronic address: [email protected].
  • 2. Nervous System Development and Homeostasis Laboratory, the Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
  • 3. School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, The British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas' Hospital, London, SE1 7EH, UK.
  • 4. Proteomics Facility, Centre of Excellence for Mass Spectrometry, King's College London, The James Black Centre, Denmark Hill Campus, London, SE5 9NU, UK.
  • 5. School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, The British Heart Foundation Centre of Excellence, James Black Centre, 125 Coldharbour Lane, London, SE5 9NU, UK.
  • 6. Institute of Structural and Molecular Biology, University College London, London, WC1E 6BT, UK; Research Department of Structural and Molecular Biology, Division of Biosciences, University College London, London, WC1E 6BT, UK; Department of Biological Sciences, Birkbeck, University of London, London, WC1E 7HX, UK.
  • 7. School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, The British Heart Foundation Centre of Excellence, The Rayne Institute, St Thomas' Hospital, London, SE1 7EH, UK. Electronic address: [email protected].
PMID: 42097034 DOI: 10.1016/j.redox.2026.104196
Abstract

Thiol redox sensors in proteins are emerging as key therapeutic targets, as they govern fundamental signalling pathways and provide crucial sites for covalent drug development. A key mediator of their function is the presence of redox-active disulphides, which act as molecular switches due to their ability to induce reversible protein conformational changes. However, despite their importance in cellular regulation and therapeutic relevance, only a limited number of redox-active disulphides have been identified to date. To address this, we developed ReDisulphID, a structural bioinformatics platform that systematically identifies druggable redox-active disulphides. Using this platform, we discovered novel druggable redox sensors in MLYCD, TFIIB, and PEPD. Functional analysis of PEPD revealed that its redox sensor activates the tumour suppressor p53. Furthermore, we identified a compound that activates p53 through direct thiol modification of the sensor in PEPD, demonstrating how ReDisulphID can advance the discovery of protein redox sensors and support thiol-targeted drug development.

Keywords
Disulphide; PEPD; Redox sensor; Thiol; p53.
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