Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 8, Issue 370, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aaf2140
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Funding
- Interministerial Comission of Science and Technology (CICYT) [SAF2010-14912, SAF2013-47975-R, CTQ2011-22514]
- European Research Council [334763]
- Comunidad de Madrid [S-BIO-0214-2006, S2010-BMD-2457, S2010/BMD-2332]
- Fundacion Genoma Espana
- Fundacion Cientifica of the Asociacion Espanola Contra el Cancer
- Fundacion Ramon Areces
- [PT13/0001]
- European Research Council (ERC) [334763] Funding Source: European Research Council (ERC)
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Modulating T cell activation is critical for treating autoimmune diseases but requires avoiding concomitant opportunistic infections. Antigen binding to the T cell receptor (TCR) triggers the recruitment of the cytosolic adaptor protein Nck to a proline-rich sequence in the cytoplasmic tail of the TCR's CD3 epsilon subunit. Through virtual screening and using combinatorial chemistry, we have generated an orally available, low-molecular weight inhibitor of the TCR-Nck interaction that selectively inhibits TCR-triggered T cell activation with an IC50 (median inhibitory concentration) similar to 1 nM. By modulating TCR signaling, the inhibitor prevented the development of psoriasis and asthma and, furthermore, exerted a long-lasting therapeutic effect in a model of autoimmune encephalomyelitis. However, it did not prevent the generation of a protective memory response against a mouse pathogen, suggesting that the compound might not exert its effects through immunosuppression. These results suggest that inhibiting an immediate TCR signal has promise for treating a broad spectrum of human T cell-mediated autoimmune and inflammatory diseases.
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