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J. Biol. Chem., Vol. 278, Issue 43, 41734-41741, October 24, 2003

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Aurintricarboxylic Acid Blocks in Vitro and in Vivo Activity of YopH, an Essential Virulent Factor of Yersinia pestis, the Agent of Plague^*

Fubo Liang, Zhonghui Huang, Seung-Yub Lee, Jiao Liang, Maya I. Ivanov¶, Andres Alonso||, James B. Bliska¶, David S. Lawrence**, Tomas Mustelin||, and Zhong-Yin Zhang**

From the Departments of Molecular Pharmacology and ^**Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, the ^¶Department of Molecular Genetics and Microbiology and Center for Infectious Diseases, State University of New York at Stony Brook, New York 11794, and ^||The Burnham Institute, La Jolla, California 92037

Yersinia are causative agents in human diseases ranging from gastrointestinal syndromes to Bubonic Plague. There is increasing risk of misuse of infectious agents, such as Yersinia pestis, as weapons of terror as well as instruments of warfare for mass destruction. YopH is an essential virulence factor whose protein-tyrosine phosphatase (PTP) activity is required for Yersinia pathogenicity. Consequently, there is considerable interest in developing potent and selective YopH inhibitors as novel anti-plague agents. We have screened a library of 720 structurally diverse commercially available carboxylic acids and identified 26 YopH inhibitors with IC₅₀ values below 100 µM. The most potent and specific YopH inhibitor is aurintricarboxylic acid (ATA), which exhibits a K_i value of 5 nM for YopH and displays 6–120-fold selectivity in favor of YopH against a panel of mammalian PTPs. To determine whether ATA can block the activity of YopH in a cellular context, we have examined the effect of ATA on T-cell signaling in human Jurkat cells transfected with YopH. We show that YopH severely decreases the T-cell receptor-induced cellular tyrosine phosphorylation, ERK1/2 activity, and interleukin-2 transcriptional activity. We demonstrate that ATA can effectively block the inhibitory activity of YopH and restore normal T-cell function. These results provide a proof-of-concept for the hypothesis that small molecule inhibitors that selectively target YopH may be therapeutically useful. In addition, it is expected that potent and selective YopH inhibitors, such as ATA, should be useful reagents to delineate YopH's cellular targets in plague and other pathogenic conditions caused by Yersinia infection.

Received for publication, July 3, 2003 , and in revised form, July 26, 2003.

^* This work was supported by National Institutes of Health Grants AI43389 (to J. B. B.) and AI48506 and the G. Harold and Leila Y. Mathers Charitable Foundation (to Z.-Y. Z.). 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.

Both authors contributed equally to this work.

An Irma T. Hirschl Career Scientist. To whom correspondence should be addressed. Tel.: 718-430-4288; Fax: 718-430-8922; E-mail: zyzhang{at}aecom.yu.edu.

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