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