Bisbenzimidazole derivatives as potent inhibitors of the trypsin-like sites of the immunoproteasome core particle

Abstract

In this study, a monomeric (MB) and a dimeric (DB) bisbenzimidazoles were identified as novel proteasome inhibitors of the trypsin-like activity located on β2c sites of the constitutive 20S proteasome (IC50 values at 2-4 μM range). Remarkably, they were further shown to be 100- and 200-fold more potent inhibitors of the immunoproteasome trypsin-like activity (β2i sites, IC50=24 nM) than of the homologous constitutive activity. Molecular models of inhibitor/enzyme complexes in the two types of trypsin-like sites and corresponding computed binding energy values corroborated kinetic data. Different binding modes were suggested for MB and DB to the β2c and β2i trypsic sites. Each pointed to better contacts of the ligand inside the β2i active site than for β2c site. MB and DB represent the first selective inhibitors of the immunoproteasome trypsin-like activity described to date and can be considered as prototypes for inhibiting this activity.

Keywords: Bisbenzimidazole derivatives; Constitutive proteasome; Immunoproteasome; In silico docking; Specific inhibitors of the trypsin-like sites.