In rheumatoid arthritis and Crohn's disease, the immune system overreacts, provoking too much inflammation. One method of treatment is to inhibit the immune protein that incites inflammation, called tumor necrosis factor (TNF). Currently available anti-TNF therapeutics have made a significant difference to patients, but are costly to manufacture and require an I.V. or injection. Sunesis Pharmaceuticals of South San Francisco, in collaboration with Biogen Idec, is researching small molecules that will inhibit TNF. The advantage of using small molecules is that they can be administered orally, and be produced much less expensively.

A team of scientists from Sunesis used macromolecular crystallography beam lines facilities at Stanford Synchrotron Radiation Laboratory to determine the structure of a potential TNF small-molecule inhibitor. X-ray diffraction studies showed that the small molecule had migrated into the center of TNF, where TNF's three subunits normally join. The small molecule then dislodged one of the three subunits, completely disrupting TNF. Turning a protein from a trimer (three parts) into a dimer (two parts) is an unusual, but clearly effective, method of inhibiting the action of a molecule.

This research enables pharmaceutical companies to identify properties of small molecules in a systematic path towards the identification of the substances that have the most potent inhibitory effects.

To learn more about this research see the full scientific highlight at:
http://www-ssrl.slac.stanford.edu/research/highlights_archive/tnf-alpha.html

He, M.M., Smith, A.S., Oslob, J.D., Flanagan, W.M., Braisted, A.C., Whitty, A., Cancilla, M.T., Wang, J., Lugovskoy, A.A., Yoburn, J.C., Fung, A.D., Farrington, G., Eldredge, J.K., Day, E.S., Cruz, L.A., Cachero, T.G., Miller, S.K., Friedman, J.E., Choong, I.C., Cunningham, B.C. Small-molecule inhibition of TNF-alpha. Science v310 pp.1022-1025, 2005