ABSTRACT
ß-Glucocerebrosidase deficiency leads to Gaucher disease and is a potential marker of Parkinson's disease. We have identified N-octyl conduritol aziridine as a potent and specific covalent inactivator of GBA1 in living cells. This compound is a promising lead towards a positron emission tomography probe intended to image GBA1 activity.
Subject(s)
Aziridines/chemistry , Aziridines/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Glucosylceramidase/antagonists & inhibitors , Inositol/analogs & derivatives , Alkylation , Aziridines/chemical synthesis , Aziridines/pharmacokinetics , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Gaucher Disease/enzymology , Glucosylceramidase/metabolism , HeLa Cells , Humans , Imino Pyranoses/chemical synthesis , Imino Pyranoses/chemistry , Imino Pyranoses/pharmacokinetics , Imino Pyranoses/pharmacology , Inositol/chemical synthesis , Inositol/chemistry , Inositol/pharmacokinetics , Inositol/pharmacology , Parkinson Disease/enzymologyABSTRACT
2-Deoxy-2-fluoroglycosides bearing dibenzyl phosphate and phosphonate aglycones were synthesised and tested as covalent inactivators of several retaining α- and ß-glycosidases. ß-d-Gluco-, -manno- and -galacto-configured benzyl-benzylphosphonate derivatives efficiently inactivated ß-gluco-, ß-manno- and ß-galactosidases, while α-gluco- and α-manno-configured phosphate and phosphonate derivatives served instead as slow substrates.
