HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 278, Issue 28, 25990-25997, July 11, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/28/25990    most recent M301232200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Soelaiman, S. Articles by Tang, W.-J. Search for Related Content PubMed PubMed Citation Articles by Soelaiman, S. Articles by Tang, W.-J. Social Bookmarking                      What's this?

Structure-based Inhibitor Discovery against Adenylyl Cyclase Toxins from Pathogenic Bacteria That Cause Anthrax and Whooping Cough^*

Sandriyana Soelaiman  , Binqing Q. Wei  ¶, Pamela Bergson , Young-Sam Lee ||, Yuequan Shen , Milan Mrksich ||, Brian K. Shoichet **  and Wei-Jen Tang  

From the Ben-May Institute for Cancer Research, The University of Chicago, Chicago, Illinois 60637, the ^¶Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, Illinois 60611, the ^||Department of Chemistry, The University of Chicago, Chicago, Illinois 60637, and the ^**Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143

Edema factor (EF) and CyaA are adenylyl cyclase toxins secreted by pathogenic bacteria that cause anthrax and whooping cough, respectively. Using the structure of the catalytic site of EF, we screened a data base of commercially available, small molecular weight chemicals for those that could specifically inhibit adenylyl cyclase activity of EF. From 24 compounds tested, we have identified one quinazoline compound, ethyl 5-aminopyrazolo[1,5-a]quinazoline-3-carboxylate, that specifically inhibits adenylyl cyclase activity of EF and CyaA with 20 µM K_i. This compound neither affects the activity of host resident adenylyl cyclases type I, II, and V nor exhibits promiscuous inhibition. The compound is a competitive inhibitor, consistent with the prediction that it binds to the adenine portion of the ATP binding site on EF. EF is activated by the host calcium sensor, calmodulin. Surface plasmon resonance spectroscopic analysis shows that this compound does not affect the binding of calmodulin to EF. This compound is dissimilar from a previously described, non-nucleoside inhibitor of host adenylyl cyclase. It may serve as a lead to design antitoxins to address the role of adenylyl cyclase toxins in bacterial pathogenesis and to fight against anthrax and whooping cough.

Received for publication, February 4, 2003 , and in revised form, March 25, 2003.

^* This research was supported by National Institutes of Health Grants GM62548 and GM53459, and an American Heart Association Established Investigator Award (to W.-J. T.), National Institutes of Health Grant 59957 (to B. K. S.), and Defense Advanced Research Projects Agency Grant N00173-01-G010 and National Science Foundation Grant DMR-9808595 (to M. M.). 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.

To whom correspondence may be addressed: Dept. of Pharmaceutical Chemistry, University of California, Genentech Hall, 600 16th St., San Francisco, CA 94143. E-mail: shoichet{at}cgl.ucsf.edu.

To whom correspondence may be addressed: Ben-May Inst. for Cancer Research, The University of Chicago, 924 East 57th St., Chicago, IL 60637. E-mail: wtang{at}midway.uchicago.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				M. Gottle, S. Dove, P. Steindel, Y. Shen, W.-J. Tang, J. Geduhn, B. Konig, and R. Seifert Molecular Analysis of the Interaction of Bordetella pertussis Adenylyl Cyclase with Fluorescent Nucleotides Mol. Pharmacol., September 1, 2007; 72(3): 526 - 535. [Abstract] [Full Text] [PDF]

				J. Hong, R. C. Doebele, M. W. Lingen, L. A. Quilliam, W.-J. Tang, and M. R. Rosner Anthrax Edema Toxin Inhibits Endothelial Cell Chemotaxis via Epac and Rap1 J. Biol. Chem., July 6, 2007; 282(27): 19781 - 19787. [Abstract] [Full Text] [PDF]

				A. M. Firoved, M. Moayeri, J. F. Wiggins, Y. Shen, W.-J. Tang, and S. H. Leppla Anthrax Edema Toxin Sensitizes DBA/2J Mice to Lethal Toxin Infect. Immun., May 1, 2007; 75(5): 2120 - 2125. [Abstract] [Full Text] [PDF]

				K. Sherer, Y. Li, X. Cui, and P. Q. Eichacker Lethal and Edema Toxins in the Pathogenesis of Bacillus anthracis Septic Shock: Implications for Therapy Am. J. Respir. Crit. Care Med., February 1, 2007; 175(3): 211 - 221. [Abstract] [Full Text] [PDF]

				A. M. Firoved, G. F. Miller, M. Moayeri, R. Kakkar, Y. Shen, J. F. Wiggins, E. M. McNally, W.-J. Tang, and S. H. Leppla Bacillus anthracis Edema Toxin Causes Extensive Tissue Lesions and Rapid Lethality in Mice Am. J. Pathol., November 1, 2005; 167(5): 1309 - 1320. [Abstract] [Full Text] [PDF]

				H. Barth, K. Aktories, M. R. Popoff, and B. G. Stiles Binary Bacterial Toxins: Biochemistry, Biology, and Applications of Common Clostridium and Bacillus Proteins Microbiol. Mol. Biol. Rev., September 1, 2004; 68(3): 373 - 402. [Abstract] [Full Text] [PDF]

				Q. Guo, Y. Shen, N. L. Zhukovskaya, J. Florian, and W.-J. Tang Structural and Kinetic Analyses of the Interaction of Anthrax Adenylyl Cyclase Toxin with Reaction Products cAMP and Pyrophosphate J. Biol. Chem., July 9, 2004; 279(28): 29427 - 29435. [Abstract] [Full Text] [PDF]

				A. Gille, G. H. Lushington, T.-C. Mou, M. B. Doughty, R. A. Johnson, and R. Seifert Differential Inhibition of Adenylyl Cyclase Isoforms and Soluble Guanylyl Cyclase by Purine and Pyrimidine Nucleotides J. Biol. Chem., May 7, 2004; 279(19): 19955 - 19969. [Abstract] [Full Text] [PDF]

				Y. Shen, N. L. Zhukovskaya, M. I. Zimmer, S. Soelaiman, P. Bergson, C.-R. Wang, C. S. Gibbs, and W.-J. Tang Selective inhibition of anthrax edema factor by adefovir, a drug for chronic hepatitis B virus infection PNAS, March 2, 2004; 101(9): 3242 - 3247. [Abstract] [Full Text] [PDF]

				M. S. Sarac, J. R. Peinado, S. H. Leppla, and I. Lindberg Protection against Anthrax Toxemia by Hexa-D-Arginine In Vitro and In Vivo Infect. Immun., January 1, 2004; 72(1): 602 - 605. [Abstract] [Full Text] [PDF]