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

J Med Chem. 2015 Jul 23;58(14):5674-83. doi: 10.1021/acs.jmedchem.5b00778. Epub 2015 Jul 14.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Computer Simulation
  • Drug Discovery*
  • Humans
  • Models, Molecular
  • Protein Binding / drug effects
  • Protein Conformation
  • Receptors, Tumor Necrosis Factor / metabolism
  • Small Molecule Libraries / metabolism
  • Small Molecule Libraries / pharmacology*
  • TNF Receptor-Associated Factor 6 / chemistry
  • TNF Receptor-Associated Factor 6 / metabolism*

Substances

  • Receptors, Tumor Necrosis Factor
  • Small Molecule Libraries
  • TNF Receptor-Associated Factor 6