Editors' ChoiceImmunology

Inhibiting pathways instead of molecules

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Science's STKE  28 Sep 1999:
Vol. 1999, Issue 1, pp. tw9
DOI: 10.1126/stke.1999.1.tw9

One of the medically important roles that the phosphatase calcineurin plays in regulating T cell responses is the dephospho-rylation of the transcription factor NFAT, which then can move into the nucleus and initiate transcription and cell activation. Current immunosuppressive drugs inhibit calcineurin, and therefore inhibit all of its functions, which may contribute to the known toxicity of the drugs. Aramburu et al. have made a more specific inhibitor of the NFAT activation pathway by identification of a peptide that binds with high affinity to the site on calcineurin to which NFAT binds, thereby inhibiting the association of the two proteins and specifically blocking only the NFAT pathway in the cell. This result demonstrates that interaction sites may make good targets for specifically inhibiting a particular signaling pathway and provide alternatives for the development of therapeutics.

Aramburu, J., Yaffe, M.B., López-Rodríguez, C., Cantley, L.C., Hogan, P.G., and Rao, A. (1999) Affinity-driven peptide selection of an NFAT inhibitor more selective than cyclosporin A. Science 285: 2129-2133. [Abstract] [Full Text]