Discovery of Selective Inhibitors of Endoplasmic Reticulum Aminopeptidase 1.

ABSTRACT: ERAP1 is an endoplasmic reticulum-resident zinc aminopeptidase that plays an important role in the immune system by trimming peptides for loading onto major histocompatibility complex proteins. Here, we report discovery of the first inhibitors selective for ERAP1 over its paralogues ERAP2 and IRAP. Compound 1 (N-(N-(2-(1H-indol-3-yl)ethyl)carbamimidoyl)-2,5-difluorobenzenesulfonamide) and compound 2 (1-(1-(4-acetylpiperazine-1-carbonyl)cyclohexyl)-3-(p-tolyl)urea) are competitive inhibitors of ERAP1 aminopeptidase activity. Compound 3 (4-methoxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid) allosterically activates ERAP1's hydrolysis of fluorogenic and chromogenic amino acid substrates but competitively in

SUBMITTER: Maben Z 

PROVIDER: S-EPMC8218592 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature