Structure-Based Development of a Protein鈥揚rotein Interaction Inhibitor Targeting Tumor Necrosis Factor Receptor-Associated Factor 6

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• 作者：Jun Moriya ; Koh Takeuchi ; Kenji Tai ; Kenzo Arai ; Naoki Kobayashi ; Naoki Yoneda ; Yoshifumi Fukunishi ; Atsushi Inoue ; Miho Kihara ; Takumi Murakami ; Kenichi Chiba ; Ichio Shimada
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：July 23, 2015
• 年：2015
• 卷：58
• 期：14
• 页码：5674-5683
• 全文大小：560K
• ISSN：1520-4804

文摘

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鈥損rotein interactions (PPIs), a potent inhibitor that surpasses the affinity of the TRAF6鈥揟NFRSF interactions has not been developed. We developed a small-molecule PPI inhibitor of TRAF6鈥揟NFRSF 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鈥揟NFRSF interaction. Structural characterization of the TRAF6鈥揟RI4 complex revealed that TRI4 supplants key interactions in the TRAF6鈥揟NFRSF interfaces. In addition, some TRAF6鈥揟RI4 interactions extend beyond the TRAF6鈥揟NFRSF 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.