Small molecule inhibitors of anthrax edema factor

• Published in: Bioorganic & medicinal chemistry letters Vol. 28; no. 2; pp. 134 - 139
• Main Authors: Jiao, Guan-Sheng, Kim, Seongjin, Moayeri, Mahtab, Thai, April, Cregar-Hernandez, Lynne, McKasson, Linda, O'Malley, Sean, Leppla, Stephen H., Johnson, Alan T.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15.01.2018
• Subjects: Animals; Anthrax; Anthrax - drug therapy; Antigens, Bacterial - pharmacology; Bacillus anthracis - drug effects; Bacterial Toxins - antagonists & inhibitors; Bacterial Toxins - pharmacology; Covalent inhibitor; Cyclic AMP - antagonists & inhibitors; Cyclic AMP - biosynthesis; Dose-Response Relationship, Drug; Edema factor; Humans; Mice; Molecular Structure; Protein Kinases - metabolism; RAW 264.7 Cells; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Structure-Activity Relationship; Edema factor; Anthrax; Covalent inhibitor
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2017.11.040

[Display omitted] Anthrax is a highly lethal disease caused by the Gram-(+) bacteria Bacillus anthracis. Edema toxin (ET) is a major contributor to the pathogenesis of disease in humans exposed to B. anthracis. ET is a bipartite toxin composed of two proteins secreted by the vegetative bacteria, edema factor (EF) and protective antigen (PA). Our work towards identifying a small molecule inhibitor of anthrax edema factor is the subject of this letter. First we demonstrate that the small molecule probe 5′-Fluorosulfonylbenzoyl 5′-adenosine (FSBA) reacts irreversibly with EF and blocks enzymatic activity. We then show that the adenosine portion of FSBA can be replaced to provide more drug-like molecules which are up to 1000-fold more potent against EF relative to FSBA, display low cross reactivity when tested against a panel of kinases, and are nanomolar inhibitors of EF in a cell-based assay of cAMP production.