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J. Biol. Chem., Vol. 280, Issue 10, 9400-9408, March 11, 2005

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Inhibition of Yersinia Tyrosine Phosphatase by Furanyl Salicylate Compounds^*

Lutz Tautz, Shane Bruckner, Sina Sareth, Andres Alonso, Jori Bogetz, Nunzio Bottini, Maurizio Pellecchia, and Tomas Mustelin

From the Infectious and Inflammatory Disease Center, The Burnham Institute, La Jolla, California 92037

To avoid detection and targeting by the immune system, the plague-causing bacterium Yersinia pestis uses a type III secretion system to deliver a set of inhibitory proteins into the cytoplasm of immune cells. One of these proteins is an exceptionally active tyrosine phosphatase termed YopH, which paralyzes lymphocytes and macrophages by dephosphorylating critical tyrosine kinases and signal transduction molecules. Because Y. pestis strains lacking YopH are avirulent, we set out to develop small molecule inhibitors for YopH. We used a novel and cost-effective approach, in which leads from a chemical library screening were analyzed and computationally docked into the crystal structure of YopH. This resulted in the identification of a series of novel YopH inhibitors with nanomolar K_i values, as well as the structural basis for inhibition. Our inhibitors lack the polar phosphate-mimicking moiety of rationally designed tyrosine phosphatase inhibitors, and they readily entered live cells and rescued them from YopH-induced tyrosine dephosphorylation, signaling paralysis, and cell death. These inhibitors may become useful for treating the lethal infection by Y. pestis.

Received for publication, November 19, 2004 , and in revised form, December 15, 2004.

^* This work was supported by Grants AI53114 and AI55789 from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed regarding in silico docking. Tel.: 858-646-3159; Fax: 858-646-3195; E-mail: mpellecchia{at}burnham.org. To whom correspondence should be addressed: The Burnham Institute, 10901 North Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-713-6270; Fax: 858-713-6274; E-mail: tmustelin{at}burnham-inst.org.

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