Small molecule inhibitors of anthrax edema factor
| Autor: | Guan-Sheng Jiao, Seongjin Kim, Linda McKasson, Lynne Cregar-Hernandez, Alan T. Johnson, Mahtab Moayeri, Sean O’Malley, Stephen H. Leppla, April Thai |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Anthrax toxin Bacterial Toxins Clinical Biochemistry Pharmaceutical Science medicine.disease_cause Biochemistry Article Anthrax Small Molecule Libraries Mice Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Edema Drug Discovery Cyclic AMP medicine Animals Humans Molecular Biology chemistry.chemical_classification Antigens Bacterial Dose-Response Relationship Drug Molecular Structure biology Chemistry Kinase Toxin Organic Chemistry biology.organism_classification Small molecule Molecular biology Adenosine Bacillus anthracis RAW 264.7 Cells 030104 developmental biology Enzyme 030220 oncology & carcinogenesis Molecular Medicine medicine.symptom Protein Kinases medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 28:134-139 |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2017.11.040 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect