Targeting TNF- Interactions

The proinflammatory cytokine, tumor necrosis factor-α (TNF-α ), plays a role in diseases such as rheumatoid arthritis, Crohn's disease, and psoriasis. TNF-α forms a homotrimer that binds to the TNF receptor to activate inflammatory responses. Although antibodies against TNF-α or soluble versions of the receptor are therapeutically effective, rationally designed small-molecule drugs that target protein-protein interactions would be useful. He et al . report on a small-molecule inhibitor that functions by dissociating the TNF-α trimer. The inhibitor binds to the intact biologically active trimer, accelerates subunit dissociation, and forms a complex with a dimer of TNF-α subunits. M. M. He, A. S. Smith, J. D. Oslob, W. M. Flanagan, A. C. Braisted, A. Whitty, M. T. Cancilla, J. Wang, A. A. Lugovskoy, J. C. Yoburn, A. D. Fung, G. Farrington, J. K. Eldredge, E. S. Day, L. A. Cruz, T. G. Cachero, S. K. Miller, J. E. Friedman, I. C. Choong, B. C. Cunningham, Small-molecule inhibition of TNF-α. Science 310 , 1022-1025 (2005). [Abstract] [Full Text]