title: Aurintricarboxylic acid blocks in vitro and in vivo activity of YopH, an essential virulent factor of Yersinia pestis, the agent of plague.
abstract: 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 mum. The most potent and specific YopH inhibitor is aurintricarboxylic acid (ATA), which exhibits a Ki 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.
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Fubo
authors.initials: F
authors.lastname: Liang
authors.forename: Zhonghui
authors.initials: Z
authors.lastname: Huang
authors.forename: Seung-Yub
authors.initials: SY
authors.lastname: Lee
authors.forename: Jiao
authors.initials: J
authors.lastname: Liang
authors.forename: Maya I
authors.initials: MI
authors.lastname: Ivanov
authors.forename: Andres
authors.initials: A
authors.lastname: Alonso
authors.forename: James B
authors.initials: JB
authors.lastname: Bliska
authors.forename: David S
authors.initials: DS
authors.lastname: Lawrence
authors.forename: Tomas
authors.initials: T
authors.lastname: Mustelin
authors.forename: Zhong-Yin
authors.initials: ZY
authors.lastname: Zhang
mesh_terms: D001312:Aurintricarboxylic Acid / Q000494:pharmacology*; D001425:Bacterial Outer Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D006801:Humans; D020128:Inhibitory Concentration 50; D007376:Interleukin-2 / Q000096:biosynthesis; D019169:Jurkat Cells; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010930:Plague / Q000382:microbiology*; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014162:Transfection; D037521:Virulence Factors / Q000037:antagonists & inhibitors* / Q000235:genetics; D015010:Yersinia pestis / Q000187:drug effects* / Q000472:pathogenicity
chemical_list: D001425:Bacterial Outer Membrane Proteins; D007376:Interleukin-2; D037521:Virulence Factors; D001312:Aurintricarboxylic Acid; D020928:Mitogen-Activated Protein Kinases; D017027:Protein Tyrosine Phosphatases; C067571:yopH protein, Yersinia