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Título

First-in-class inhibitor of the T cell receptor for the treatment of autoimmune diseases

AutorBorroto Revuelta, Aldo; Reyes-Garau, Diana; Jiménez, M. Angeles ; Carrasco, Esther ; Moreno, Beatriz; Martínez-Pasamar, Sara; Cortés, José R.; Perona, Almudena; Abia, David; Blanco, Soledad; Fuentes, Manuel; Arellano Rojo, Irene; Lobo, Juan; Heidarieh, Haleh; Rueda, Javier; Esteve, Pilar; Cibrián, Danay; Martínez-Riaño, Ana; Mendoza, Pilar; Prieto, Cristina; Calleja, Enrique; Oeste, Clara L. ; Orfao, Alberto; Fresno, Manuel; Sánchez-Madrid, Francisco; Alcamí, Antonio; Bovolenta, Paola; Martín, Pilar; Villoslada, Pablo; Morreale, Antonio; Messeguer, Ángel; Alarcón, Balbino
Fecha de publicación2016
CitaciónScience Translational Medicine 8 (2016)
ResumenModulating 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.
URIhttp://hdl.handle.net/10261/153913
DOI10.1126/scitranslmed.aaf2140
Identificadoresdoi: 10.1126/scitranslmed.aaf2140
issn: 1946-6242
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