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Title: | First-in-class inhibitor of the T cell receptor for the treatment of autoimmune diseases |
Authors: | Borroto Revuelta, Aldo ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
Issue Date: | 2016 |
Citation: | Science Translational Medicine 8 (2016) |
Abstract: | 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 CD3e 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 activationwith an IC50 (median inhibitory concentration) ~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 amouse 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 spectrumof human T cell-mediated autoimmune and inflammatory diseases. |
URI: | http://hdl.handle.net/10261/153913 |
DOI: | 10.1126/scitranslmed.aaf2140 |
Identifiers: | doi: 10.1126/scitranslmed.aaf2140 issn: 1946-6242 |
Appears in Collections: | (IQFR) Artículos (CBM) Artículos (IQAC) Artículos (IBMCC) Artículos |
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