title: Screening Identifies Thimerosal as a Selective Inhibitor of Endoplasmic Reticulum Aminopeptidase 1.
abstract: We employed virtual screening followed by in vitro evaluation to discover novel inhibitors of ER aminopeptidase 1, an important enzyme for the human adaptive immune response that has emerged as an attractive target for cancer immunotherapy and the control of autoimmunity. Screening hits included three structurally related compounds carrying the (E)-N'-((1H-indol-3-yl)methylene)-1H-pyrazole-5-carbohydrazide scaffold and (2-carboxylatophenyl)sulfanyl-ethylmercury as novel ERAP1 inhibitors. The latter, also known as thimerosal, a common component in vaccines, was found to inhibit ERAP1 in the submicromolar range and to present strong selectivity versus the homologous aminopeptidases ERAP2 and IRAP. Cell-based analysis indicated that thimerosal can effectively reduce ERAP1-dependent cross-presentation by dendritic cells in a dose-dependent manner.
authors.affiliation: National Center for Scientific Research Demokritos , Agia Paraskevi GR-15310, Athens, Greece.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Stamogiannos
authors.affiliation: National Center for Scientific Research Demokritos , Agia Paraskevi GR-15310, Athens, Greece.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Papakyriakou
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité1151; Université Paris Descartes, Sorbonne Paris Cité; Centre National de la Recherche Scientifique, Unité 8253 , 75015 Paris, France.
authors.forename: Francois-Xavier
authors.initials: FX
authors.lastname: Mauvais
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité1151; Université Paris Descartes, Sorbonne Paris Cité; Centre National de la Recherche Scientifique, Unité 8253 , 75015 Paris, France.
authors.forename: Peter
authors.initials: P
authors.lastname: van Endert
authors.affiliation: National Center for Scientific Research Demokritos , Agia Paraskevi GR-15310, Athens, Greece.
authors.forename: Efstratios
authors.initials: E
authors.lastname: Stratikos
keywords: ERAP1; ERAP2; IRAP; aminopeptidase; antigenic peptide; docking; immune system; inhibitor