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

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.This work was supported by the “Cooperative Research Program grants for Agriculture Science & Technology Development (Project No. PJ907052)” funded by the Rural Development Administration, Republic of Korea and Bio-industry Technology Development Program, Ministry for Food, Agriculture, Forestry and Fisheries, Republic of Korea (111079-3). The chemical library used in this study was kindly provided by Korea Chemical Bank of Korea Research Institute of Chemical Technology and the compound No.109 and 112 were donated to Korea Chemical Bank by Shi-Yong Ryu and the compound No.106 and 200 were donated to Korea Chemical Bank by Young-Sup Kim