title: Proteolytic assay-based screening identifies a potent inhibitor of anthrax lethal factor.
abstract: Anthrax lethal factor (LF), a Zn(2+)-dependent metalloprotease, is a key virulence component of anthrax toxin. Here, we used proteolytic assay-based screening to identify novel LF inhibitors from a naturally extracted chemical library. The screening identified four compounds that inhibited in vitro proteolytic activity of LF with an IC(50) of low micromolar range (11-20 μM). Three of these compounds were toxic to the mouse macrophage-like cell line, RAW 264.7. Compound 200 was non-toxic, however, and successfully protected Raw 264.7 cells from a lethal toxin challenge with an IC(50) of 39.2 μM. We also identified possible binding modes of compound 200 by molecular docking.
authors.affiliation: Department of Chemistry and Research Institute of Natural Sciences, Hanyang University, Seoul 133-761, Republic of Korea.
authors.forename: Hae-Chul
authors.initials: HC
authors.lastname: Park
authors.forename: So-Ra
authors.initials: SR
authors.lastname: Sung
authors.forename: Su Min
authors.initials: SM
authors.lastname: Lim
authors.forename: Jong-Sun
authors.initials: JS
authors.lastname: Lee
authors.forename: Sung-Kun
authors.initials: SK
authors.lastname: Kim
authors.forename: Moon-Young
authors.initials: MY
authors.lastname: Yoon
mesh_terms: D000818:Animals; D000881:Anthrax / Q000382:microbiology; D000942:Antigens, Bacterial / Q000737:chemistry; D001408:Bacillus anthracis / Q000187:drug effects / Q000201:enzymology*; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001665:Binding Sites; D002460:Cell Line; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D059748:Proteolysis; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; C030325:anthrax toxin