Discovery of a small molecule that inhibits the interaction of anthrax edema factor with its cellular activator, calmodulin.
The catalytic efficiency of adenylyl cyclase activity of edema factor (EF) from Bacillus anthracis is enhanced by approximately 1000-fold upon its binding to mammalian protein calmodulin (CaM). A tandem cell-based and protein binding-based screen of a 10,000 member library identified a molecule that inhibits the EF-CaM interaction and therefore the adenylyl cyclase activity. A combination of fluorescence spectroscopy and photolabeling studies showed that the molecule targets the CaM binding region of EF. A series of related compounds were synthesized and evaluated to identify one compound, 4-[4-(4-nitrophenyl)-thiazolylamino]-benzenesulfonamide, that maintained activity against EF but showed minimal toxicity to two cultured cell lines. This compound represents an important reagent to study the role of EF in anthrax pathology and may represent a drug lead against anthrax infection.
Department of Chemistry and Institute of Biophysical Dynamics, The University of Chicago, Chicago, Illinois 60637, USA.
Young-Sam
YS
Lee
Pamela
P
Bergson
Wei Song
WS
He
Milan
M
Mrksich
Wei-Jen
WJ
Tang
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D000881:Anthrax / Q000188:drug therapy; D000942:Antigens, Bacterial; D001408:Bacillus anthracis / Q000737:chemistry / Q000378:metabolism; D001427:Bacterial Toxins; D002147:Calmodulin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D006224:Cricetinae; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D020349:Surface Plasmon Resonance; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D000096926:Benzenesulfonamides
D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D002147:Calmodulin; D008024:Ligands; D013449:Sulfonamides; D013844:Thiazoles; C496214:4-(4-(3,4-dichlorophenyl)thiazolylamino)benzenesulfonamide; D000096926:Benzenesulfonamides; C030325:anthrax toxin