Anthrax is an acute infectious disease caused by the bacterium Bacillus anthracis, one of the most dangerous bioterror agents. The lethal factor enzyme is secreted by B. anthracis as part of a tripartite exotoxin and is chiefly responsible for anthrax-related cytotoxicity. The bacilli are susceptible to antibiotics, but early administration is crucial as there is no antidote against the toxin itself. Moreover, LF can remain in the system for weeks after antibiotics have eradicated B. anthracis from the body, and host death can result from residual toxemia. Although LF is an attractive target for rational drug design, relatively few published inhibitors have demonstrated activity in cell-based assays and no LF inhibitor is currently available as a preventive or therapeutic agent. Here, we have identified key optimization principles of LF inhibitors based on CoMFA and CoMSIA models of several published compound series and a previously validated, comprehensive pharmacophore hypothesis. The principles, covering all three subsites of the LF active site, are being applied in our laboratory to increase potency of novel LF HTS hits.

Optimization strategy for anthrax toxin lethal factor (LF) inhibitors based on 3D-QSAR and pharmacophore models

247th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.