Letter abstract
Nature Chemical Biology 1, 371 - 376 (2005)
Published online: 30 October 2005 | doi:10.1038/nchembio744
Monocarboxylate transporter MCT1 is a target for immunosuppression
Clare M Murray1, Raymond Hutchinson1, John R Bantick2, Graham P Belfield3, Amanda D Benjamin1, Diana Brazma1,5, Robert V Bundick1, I David Cook1,5, Robert I Craggs1, Susan Edwards1, Leslie R Evans3,5, Richard Harrison2, Elain Holness1, Andrew P Jackson3, Clive G Jackson3, Lee P Kingston2, Matthew W D Perry2, Andrew R J Ross3, Paul A Rugman1, Sasvinder S Sidhu1, Michael Sullivan3,5, David A Taylor-Fishwick1,5, P Craig Walker3, Yvonne M Whitehead1, David J Wilkinson2, Andrew Wright4 & David K Donald2
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.
- Department of Discovery BioScience, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, UK.
- Department of Medicinal Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, UK.
- Department of Molecular Biology, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, UK.
- Departments of Physical and Metabolic Science, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, UK.
- Present addresses: Department of Academic Haematology, Royal Free and University College Medical School, London NW3 2PF, UK (D.B.); Global Discovery Enabling Capabilities and Sciences, AstraZeneca R&D Alderley Park, Cheshire SK10 4TG, UK (I.D.C); Delta Biotechnology Ltd., Castle Court, 59 Castle Boulevard, Nottingham NG7 1ED, UK (L.R.E.); Advanced Science and Technology Lab, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, UK (M.S.); and Cell and Molecular Biology, Diabetes Research Institute, Eastern Virginia Medical School, Norfolk, Virginia 23510, USA (D.A.T.F.).
Correspondence to: Clare M Murray1 e-mail: Clare.Murray@astrazeneca.com
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