title: First-in-class inhibitor of the T cell receptor for the treatment of autoimmune diseases.
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 CD3ε 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) ~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.
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain.
authors.forename: Aldo
authors.initials: A
authors.lastname: Borroto
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain.
authors.forename: Diana
authors.initials: D
authors.lastname: Reyes-Garau
authors.affiliation: Instituto de Química Física Rocasolano, CSIC, Madrid, Spain.
authors.forename: M Angeles
authors.initials: MA
authors.lastname: Jiménez
authors.affiliation: Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Carrasco
authors.affiliation: Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS)-Hospital Clinic, Barcelona, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Moreno
authors.affiliation: Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS)-Hospital Clinic, Barcelona, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Martínez-Pasamar
authors.affiliation: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
authors.forename: José R
authors.initials: JR
authors.lastname: Cortés
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain.
authors.forename: Almudena
authors.initials: A
authors.lastname: Perona
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Abia
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain.
authors.forename: Soledad
authors.initials: S
authors.lastname: Blanco
authors.affiliation: Centro de Investigación del Cáncer, University of Salamanca-CSIC, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Fuentes
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Arellano
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Lobo
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain.
authors.forename: Haleh
authors.initials: H
authors.lastname: Heidarieh
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Rueda
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Esteve
authors.affiliation: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
authors.forename: Danay
authors.initials: D
authors.lastname: Cibrián
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Martinez-Riaño
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Mendoza
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Prieto
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Calleja
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain.
authors.forename: Clara L
authors.initials: CL
authors.lastname: Oeste
authors.affiliation: Centro de Investigación del Cáncer, University of Salamanca-CSIC, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Orfao
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Fresno
authors.affiliation: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Sánchez-Madrid
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Alcamí
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain.
authors.forename: Paola
authors.initials: P
authors.lastname: Bovolenta
authors.affiliation: Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Martín
authors.affiliation: Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS)-Hospital Clinic, Barcelona, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Villoslada
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Morreale
authors.affiliation: Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Messeguer
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain. balarcon@cbm.csic.es.
authors.forename: Balbino
authors.initials: B
authors.lastname: Alarcon
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D015195:Drug Design; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007165:Immunosuppression Therapy; D020128:Inhibitory Concentration 50; D008024:Ligands; D008213:Lymphocyte Activation; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D000072417:Protein Domains; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors* / Q000276:immunology; D015398:Signal Transduction; D020349:Surface Plasmon Resonance; D013601:T-Lymphocytes / Q000166:cytology
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D008024:Ligands; D011948:Receptors, Antigen, T-Cell