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Monocarboxylate transporter MCT1 is a target for immunosuppression - Nature Chemical Biology

  • ️Donald, David K
  • ️Sun Oct 30 2005

Abstract

Current immunosuppressive therapies act on T lymphocytes by modulation of cytokine production, modulation of signaling pathways or by inhibition of the enzymes of nucleotide biosynthesis. We have identified a previously unknown series of immunomodulatory compounds that potently inhibit human and rat T lymphocyte proliferation in vitro and in vivo in immune-mediated animal models of disease, acting by a novel mechanism. Here we identify the target of these compounds, the monocarboxylate transporter MCT1 (SLC16A1)1, using a strategy of photoaffinity labeling and proteomic characterization. We show that inhibition of MCT1 during T lymphocyte activation results in selective and profound inhibition of the extremely rapid phase of T cell division essential for an effective immune response. MCT1 activity, however, is not required for many stages of lymphocyte activation, such as cytokine production, or for most normal physiological functions. By pursuing a chemistry-led target identification strategy, we have discovered that MCT1 is a previously unknown target for immunosuppressive therapy and have uncovered an unsuspected role for MCT1 in immune biology.

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Acknowledgements

We thank A. Baines for helpful advice on protein purification from red blood cells and K. Wood, D. Cantrell and A. Halestrap for helpful advice and discussions. We thank K. Jolley for technical assistance in analyzing glucose metabolites by GC-MS, E. Newboult and S. Cartlidge for tumor cell proliferation studies and M. Erlansson and L. Jansson for the CIA model. We gratefully acknowledge the assistance of S. Guile and R. Mohammed in collating the chemical synthesis and analysis information.

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Author notes

  1. Diana Brazma

    Present address: Department of Academic Haematology, Royal Free and University College Medical School, London, NW3 2PF, UK

  2. I David Cook

    Present address: Global Discovery Enabling Capabilities and Sciences, AstraZeneca R&D Alderley Park, Cheshire, SK10 4TG, UK

  3. Leslie R Evans

    Present address: Delta Biotechnology Ltd., Castle Court, 59 Castle Boulevard, Nottingham, NG7 1ED, UK

  4. Michael Sullivan

    Present address: Advanced Science and Technology Lab, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire, LE11 5RH, UK

  5. David A Taylor-Fishwick

    Present address: Cell and Molecular Biology, Diabetes Research Institute, Eastern Virginia Medical School, Norfolk, Virginia, 23510, USA

Authors and Affiliations

  1. Department of Discovery BioScience, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, LE11 5RH, Leicestershire, UK

    Clare M Murray, Raymond Hutchinson, Amanda D Benjamin, Diana Brazma, Robert V Bundick, I David Cook, Robert I Craggs, Susan Edwards, Elain Holness, Paul A Rugman, Sasvinder S Sidhu, David A Taylor-Fishwick & Yvonne M Whitehead

  2. Department of Medicinal Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, LE11 5RH, Leicestershire, UK

    John R Bantick, Richard Harrison, Lee P Kingston, Matthew W D Perry, David J Wilkinson & David K Donald

  3. Department of Molecular Biology, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, LE11 5RH, Leicestershire, UK

    Graham P Belfield, Leslie R Evans, Andrew P Jackson, Clive G Jackson, Andrew R J Ross, Michael Sullivan & P Craig Walker

  4. Departments of Physical and Metabolic Science, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, LE11 5RH, Leicestershire, UK

    Andrew Wright

Authors

  1. Clare M Murray

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  2. Raymond Hutchinson

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  3. John R Bantick

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  4. Graham P Belfield

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  5. Amanda D Benjamin

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  6. Diana Brazma

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  7. Robert V Bundick

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  8. I David Cook

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  9. Robert I Craggs

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  10. Susan Edwards

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  11. Leslie R Evans

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  12. Richard Harrison

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  13. Elain Holness

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  14. Andrew P Jackson

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  15. Clive G Jackson

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  16. Lee P Kingston

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  17. Matthew W D Perry

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  18. Andrew R J Ross

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  19. Paul A Rugman

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  20. Sasvinder S Sidhu

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  21. Michael Sullivan

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  22. David A Taylor-Fishwick

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  23. P Craig Walker

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  24. Yvonne M Whitehead

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  25. David J Wilkinson

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  26. Andrew Wright

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  27. David K Donald

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Correspondence to Clare M Murray.

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The authors are either current or former employees of Astra Zeneca p/c.

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Murray, C., Hutchinson, R., Bantick, J. et al. Monocarboxylate transporter MCT1 is a target for immunosuppression. Nat Chem Biol 1, 371–376 (2005). https://doi.org/10.1038/nchembio744

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  • Received: 06 July 2005

  • Accepted: 03 October 2005

  • Published: 30 October 2005

  • Issue Date: December 2005

  • DOI: https://doi.org/10.1038/nchembio744

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