Novel Cell-Permeable Acyloxymethylketone Inhibitors of Asparaginyl Endopeptidase

• DOI: 10.1515/bc.2003.136
• Publication Date: 2004-09-06T16:11:23Z
• Authors: K. Loak; D. N. Li; B. Manoury; J. Billson; F. Morton; E. Hewitt; C. Watts
• Keywords: Endopeptidase

Mammalian asparaginyl endopeptidase (AEP) or legumain is a recently identified lysosomal cysteine protease belonging to clan CD. To date it has been shown be involved in antigen presentation within class II MHC positive cells and pro-protein processing. Further elucidation of the biological functions enzyme will require potent selective inhibitors thus we describe here new acyloxymethylketone AEP. The most series 2,6-dimethyl-benzoic acid 3-benzyloxycarbonylamino-4-carbamoyl-2-oxo-butyl ester (MV026630) with kobs/[I] value 1.09 x 10(5) M(-1) s(-1). At low microM concentrations this compound able enter living irreversibly inactivate We show that results inhibition AEP autoactivation perturbation processing T cell epitopes from both tetanus toxin myelin basic protein.