title: Structure-Based Development of a Protein-Protein Interaction Inhibitor Targeting Tumor Necrosis Factor Receptor-Associated Factor 6.
abstract: The interactions between tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and TNF superfamily receptors (TNFRSFs) are promising targets for rheumatoid arthritis (RA) treatment. However, due to the challenging nature of protein-protein interactions (PPIs), a potent inhibitor that surpasses the affinity of the TRAF6-TNFRSF interactions has not been developed. We developed a small-molecule PPI inhibitor of TRAF6-TNFRSF interactions using NMR and in silico techniques. The most potent compound, TRI4, exhibited an affinity higher than those of TNFRSFs and competitively inhibited a TRAF6-TNFRSF interaction. Structural characterization of the TRAF6-TRI4 complex revealed that TRI4 supplants key interactions in the TRAF6-TNFRSF interfaces. In addition, some TRAF6-TRI4 interactions extend beyond the TRAF6-TNFRSF interfaces and increase the binding affinity. Our successful development of TRI4 provides a new opportunity for RA treatment and implications for structure-guided development of PPI inhibitors.
authors.affiliation: †Eisai Product Creation Systems, Eisai Co., Ltd., Tokodai 5-1-3, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Moriya
authors.affiliation: ‡Biological Information Research Center and Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Aomi 2-3-26, Koto-ku, Tokyo 135-0064, Japan.
authors.forename: Koh
authors.initials: K
authors.lastname: Takeuchi
authors.affiliation: †Eisai Product Creation Systems, Eisai Co., Ltd., Tokodai 5-1-3, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tai
authors.affiliation: †Eisai Product Creation Systems, Eisai Co., Ltd., Tokodai 5-1-3, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Kenzo
authors.initials: K
authors.lastname: Arai
authors.affiliation: †Eisai Product Creation Systems, Eisai Co., Ltd., Tokodai 5-1-3, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kobayashi
authors.affiliation: †Eisai Product Creation Systems, Eisai Co., Ltd., Tokodai 5-1-3, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Yoneda
authors.affiliation: ‡Biological Information Research Center and Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Aomi 2-3-26, Koto-ku, Tokyo 135-0064, Japan.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Fukunishi
authors.affiliation: †Eisai Product Creation Systems, Eisai Co., Ltd., Tokodai 5-1-3, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Inoue
authors.affiliation: †Eisai Product Creation Systems, Eisai Co., Ltd., Tokodai 5-1-3, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Kihara
authors.affiliation: §Pharmacological Evaluation Unit, Tsukuba Division, Sunplanet Co., Ltd., Tokodai 5-11-1, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Murakami
authors.affiliation: †Eisai Product Creation Systems, Eisai Co., Ltd., Tokodai 5-1-3, Tsukuba-shi, Ibaraki 300-2635, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Chiba
authors.affiliation: ∥Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Ichio
authors.initials: I
authors.lastname: Shimada
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D054852:Small Molecule Libraries / Q000378:metabolism / Q000494:pharmacology*; D048029:TNF Receptor-Associated Factor 6 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D018124:Receptors, Tumor Necrosis Factor; D054852:Small Molecule Libraries; D048029:TNF Receptor-Associated Factor 6