Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 7, Issue 7, Pages 681-685Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.6b00084
Keywords
ERAP1; ERAP2; IRAP; aminopeptidase; inhibitor; immune system; antigenic peptide; docking
Categories
Funding
- European Union (EU Social Fund)
- Greek National funds through the Operational Program Education and Lifelong Learning of the National Strategic Reference Framework: Research Funding Program of the General Secretariat for Research and Technology [ERC-14]
- Fondation pour la Recherche Medicale [DEQ20130326539]
- Agence Nationale de Recherche [ANR-14-CE11-0014]
- Agence Nationale de la Recherche (ANR) [ANR-14-CE11-0014] Funding Source: Agence Nationale de la Recherche (ANR)
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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.
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