TY - JOUR
T1 - Structure-based inhibitor discovery against adenylyl cyclase toxins from pathogenic bacteria that cause anthrax and whooping cough
AU - Soelaiman, Sandriyana
AU - Wei, Binqing Q.
AU - Bergson, Pamela
AU - Lee, Young Sam
AU - Shen, Yuequan
AU - Mrksich, Milan
AU - Shoichet, Brian K.
AU - Tang, Wei Jen
PY - 2003/7/11
Y1 - 2003/7/11
N2 - 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 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 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.
AB - 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 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 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.
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U2 - 10.1074/jbc.M301232200
DO - 10.1074/jbc.M301232200
M3 - Article
C2 - 12676933
AN - SCOPUS:0037493019
SN - 0021-9258
VL - 278
SP - 25990
EP - 25997
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 28
ER -