Τίτλος:
Discovery of potent and selective inhibitors of human aminopeptidases ERAP1 and ERAP2 by screening libraries of phosphorus-containing amino acid and dipeptide analogues
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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 = 100–350 nM). 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. © 2016 Elsevier Ltd
Συγγραφείς:
Węglarz-Tomczak, E.
Vassiliou, S.
Mucha, A.
Περιοδικό:
Bioorganic and Medicinal Chemistry Letters
Εκδότης:
Elsevier Ireland Ltd
Λέξεις-κλειδιά:
alpha,beta diaminophosphonate derivative; amino acid derivative; aminopeptidase; dipeptide derivative; endoplasmic reticulum aminopeptidase 1; endoplasmic reticulum aminopeptidase 2; organophosphorus compound; phosphinic acid derivative; phosphonic acid derivative; phosphorus derivative; unclassified drug; amino acid; aminopeptidase; dipeptide; ERAP1 protein, human; ERAP2 protein, human; metal; minor histocompatibility antigen; phosphinic acid derivative; phosphonic acid derivative; phosphorous acid; protein binding, Article; binding kinetics; competitive inhibition; conformational transition; drug binding site; drug identification; drug potency; drug protein binding; drug screening; drug selectivity; drug specificity; drug structure; enzyme inhibition; enzyme regulation; human; peptide library; structure activity relation; antagonists and inhibitors; chemistry; hydrogen bond; metabolism; preclinical study, Amino Acids; Aminopeptidases; Dipeptides; Drug Evaluation, Preclinical; Humans; Hydrogen Bonding; Metals; Minor Histocompatibility Antigens; Phosphinic Acids; Phosphorous Acids; Protein Binding; Structure-Activity Relationship
DOI:
10.1016/j.bmcl.2016.06.062
