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Papers In Press, published online ahead of print April 3, 2003
Ban-May Institute for Cancer Research, The University of Chicago, Chicago, IL 60637
Corresponding Author: wtang{at}midway.uchicago.edu
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 database 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 uM Ki. 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 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, nonnucleoside inhibitor of host adenylyl cyclase. It may serve as a lead to design anti-toxin to address the role of adenylyl cyclase toxins in bacterial pathogenesis and to fight against anthrax and whooping cough.
J. Biol. Chem, 10.1074/jbc.M301232200
Submitted on February 4, 2003
Revised on March 25, 2003
Accepted on April 3, 2003
Structure-based inhibitor discovery against adenylyl cyclase toxins from pathogenic bacteria that cause anthrax and whooping cough
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