title: Discovery of potent and selective inhibitors of human aminopeptidases ERAP1 and ERAP2 by screening libraries of phosphorus-containing amino acid and dipeptide analogues.
abstract: A collection of fifty phosphonic and phosphinic acids was screened for inhibition of ERAP1 and ERAP2, the human endoplasmic reticulum aminopeptidases. The cooperative action of these enzymes is manifested by trimming a variety of antigenic precursors to be presented on the cell surface by major histocompatibility class I. The SAR studies revealed several potent compounds, particularly among the phosphinic dipeptide analogues, that were strong inhibitors of ERAP2 (Ki=100-350nM). A wide structural diversity of the applied organophosphorus compounds, predominantly non-proteinogenic analogues, allowed identification of representatives selective toward only one form of ERAP. For example, N'-substituted α,β-diaminophosphonates and phosphinates exhibited potency only toward ERAP2, which is in agreement with the P1 basic substrate-oriented specificity. Such discriminating ligands are invaluable tools for elucidating the precise role of a particular aminopeptidase in the concerted function of antigen processing and in human diseases.
authors.affiliation: Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland.
authors.forename: Ewelina
authors.initials: E
authors.lastname: Węglarz-Tomczak
authors.affiliation: Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, Zografou, 15701 Athens, Greece.
authors.forename: Stamatia
authors.initials: S
authors.lastname: Vassiliou
authors.affiliation: Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland. Electronic address: artur.mucha@pwr.edu.pl.
authors.forename: Artur
authors.initials: A
authors.lastname: Mucha
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000626:Aminopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004151:Dipeptides / Q000737:chemistry*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006860:Hydrogen Bonding; D008670:Metals / Q000737:chemistry / Q000378:metabolism; D015778:Minor Histocompatibility Antigens / Q000378:metabolism*; D010721:Phosphinic Acids / Q000737:chemistry / Q000378:metabolism*; D010757:Phosphorous Acids / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D004151:Dipeptides; D008670:Metals; D015778:Minor Histocompatibility Antigens; D010721:Phosphinic Acids; D010757:Phosphorous Acids; C570063:phosphonic acid; D000626:Aminopeptidases; C464841:ERAP1 protein, human; C503944:ERAP2 protein, human
keywords: Antigenic peptide processing; Metalloaminopeptidases; Organophosphorus inhibitors; SAR studies