Structure-based inhibitor discovery against adenylyl cyclase toxins from pathogenic bacteria that cause anthrax and whooping cough.

Abstract

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 approximately 20 microm 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.

• Authors: Sandriyana Soelaiman, Binqing Q Wei, Pamela Bergson, Young-Sam Lee, Yuequan Shen, Milan Mrksich, Brian K Shoichet, Wei-Jen Tang
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 278 Issue 28 Pg. 25990-7 (Jul 11 2003) ISSN: 0021-9258 [Print] United States
• PMID: 12676933 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adenylate Cyclase Toxin
• Calmodulin
• Enzyme Inhibitors
• Pyrazoles
• Quinazolines
• Viper Venoms
• edema factor
• ethyl 5-aminopyrazolo(1,5-a)quinazoline-3-carboxylate
• Cyclic AMP
• Adenylyl Cyclases
• Calcium

Topics

• Adenylate Cyclase Toxin (antagonists & inhibitors, chemistry)
• Adenylyl Cyclases (metabolism)
• Bacillus anthracis (metabolism, pathogenicity)
• Binding Sites
• Binding, Competitive
• Calcium (metabolism)
• Calmodulin (metabolism)
• Catalytic Domain
• Cyclic AMP (metabolism)
• Dose-Response Relationship, Drug
• Drug Design
• Enzyme Inhibitors (pharmacology)
• Kinetics
• Light
• Models, Chemical
• Models, Molecular
• Protein Binding
• Pseudomonas aeruginosa (metabolism, pathogenicity)
• Pyrazoles (chemical synthesis, pharmacology)
• Quinazolines (chemical synthesis, pharmacology)
• Scattering, Radiation
• Software
• Surface Plasmon Resonance
• Viper Venoms (antagonists & inhibitors, chemistry)