Proteolytic assay-based screening identifies a potent inhibitor of anthrax lethal factor

Microb Pathog. 2012 Aug;53(2):109-12. doi: 10.1016/j.micpath.2012.04.004. Epub 2012 Apr 26.

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.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anthrax / microbiology
  • Antigens, Bacterial / chemistry
  • Bacillus anthracis / drug effects
  • Bacillus anthracis / enzymology*
  • Bacterial Toxins / antagonists & inhibitors*
  • Bacterial Toxins / chemistry
  • Binding Sites
  • Cell Line
  • Drug Evaluation, Preclinical / methods*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Macrophages / drug effects
  • Mice
  • Molecular Structure
  • Proteolysis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology

Substances

  • Antigens, Bacterial
  • Bacterial Toxins
  • Enzyme Inhibitors
  • Small Molecule Libraries
  • anthrax toxin