title: 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.
authors.affiliation: Department of Chemistry, Moscow State University, Moscow 119991, Russia.
authors.forename: Olga N
authors.initials: ON
authors.lastname: Koroleva
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR-CNRS 8256, ERL U1164, B2A, Biological Adaptation and Ageing, Integrated Cellular Ageing and Inflammation, Molecular and Functional Enzymology, Case 256, 7 Quai St Bernard, F-75005 Paris, France.
authors.forename: The Hien
authors.initials: TH
authors.lastname: Pham
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Atelier de Bioinformatique, Case courrier 1202, 4 Place Jussieu, F 75252 Paris Cedex 05, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bouvier
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR-CNRS 8256, ERL U1164, B2A, Biological Adaptation and Ageing, Integrated Cellular Ageing and Inflammation, Molecular and Functional Enzymology, Case 256, 7 Quai St Bernard, F-75005 Paris, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Dufau
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR-CNRS 8256, ERL U1164, B2A, Biological Adaptation and Ageing, Integrated Cellular Ageing and Inflammation, Molecular and Functional Enzymology, Case 256, 7 Quai St Bernard, F-75005 Paris, France.
authors.forename: Lixian
authors.initials: L
authors.lastname: Qin
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR-CNRS 8256, ERL U1164, B2A, Biological Adaptation and Ageing, Integrated Cellular Ageing and Inflammation, Molecular and Functional Enzymology, Case 256, 7 Quai St Bernard, F-75005 Paris, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Reboud-Ravaux
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Ivanov
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia.
authors.forename: Alexei L
authors.initials: AL
authors.lastname: Zhuze
authors.affiliation: Department of Chemistry, Moscow State University, Moscow 119991, Russia.
authors.forename: Elizaveta S
authors.initials: ES
authors.lastname: Gromova
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR-CNRS 8256, ERL U1164, B2A, Biological Adaptation and Ageing, Integrated Cellular Ageing and Inflammation, Molecular and Functional Enzymology, Case 256, 7 Quai St Bernard, F-75005 Paris, France. Electronic address: mbouvier@snv.jussieu.fr.
authors.forename: Michelle
authors.initials: M
authors.lastname: Bouvier-Durand
mesh_terms: D000818:Animals; D006690:Bisbenzimidazole / Q000378:metabolism / Q000494:pharmacology*; D002154:Calpain / Q000037:antagonists & inhibitors; D020134:Catalytic Domain; D002401:Cathepsin B / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D051379:Mice; D062105:Molecular Docking Simulation; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D014357:Trypsin / Q000737:chemistry*
chemical_list: D007527:Isoenzymes; D061988:Proteasome Inhibitors; D014357:Trypsin; D002154:Calpain; D002401:Cathepsin B; D046988:Proteasome Endopeptidase Complex; D006690:Bisbenzimidazole
keywords: Bisbenzimidazole derivatives; Constitutive proteasome; Immunoproteasome; In silico docking; Specific inhibitors of the trypsin-like sites