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

Abstract

Anthrax lethal factor (LF), a Zn2+-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 IC50 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 IC50 of 39.2 μM. We also identified possible binding modes of compound 200 by molecular docking.