A Systematic Screen of FDA-Approved Drugs for Inhibitors of Biological Threat Agents

Abstract

BackgroundThe rapid development of effective medical countermeasures against potential biological threat agents is vital. Repurposing existing drugs that may have unanticipated activities as potential countermeasures is one way to meet this important goal, since currently approved drugs already have well-established safety and pharmacokinetic profiles in patients, as well as manufacturing and distribution networks. Therefore, approved drugs could rapidly be made available for a new indication in an emergency.Methodology/Principal FindingsA large systematic effort to determine whether existing drugs can be used against high containment bacterial and viral pathogens is described. We assembled and screened 1012 FDA-approved drugs for off-label broad-spectrum efficacy against Bacillus anthracis; Francisella tularensis; Coxiella burnetii; and Ebola, Marburg, and Lassa fever viruses using in vitro cell culture assays. We found a variety of hits against two or more of these biological threat pathogens, which were validated in secondary assays. As expected, antibiotic compounds were highly active against bacterial agents, but we did not identify any non-antibiotic compounds with broad-spectrum antibacterial activity. Lomefloxacin and erythromycin were found to be the most potent compounds in vivo protecting mice against Bacillus anthracis challenge. While multiple virus-specific inhibitors were identified, the most noteworthy antiviral compound identified was chloroquine, which disrupted entry and replication of two or more viruses in vitro and protected mice against Ebola virus challenge in vivo.Conclusions/SignificanceThe feasibility of repurposing existing drugs to face novel threats is demonstrated and this represents the first effort to apply this approach to high containment bacteria and viruses.

A common feature pharmacophore for FDA-approved drugs inhibiting the Ebola virus

“…These molecules were similar to the FDA benzimidazole and aminoquinoline 8, 9 compounds that were active against EBOV. Another good example is the recent in silico docking of 5.4 million drug-like compounds docked in the viral protein VP35 protein 15 .…”

“…Previously estradiol was suggested to be active in the EBOV pseudotype assay in vitro 8 . In addition, dibucaine was also retrieved (Fit value 1.58) which was also active in the EBOV pseudotype assay 8 . Amodiaquine, chloroquine, clomiphene and toremifene can be used as positive controls for future screens.…”

“…Two papers from 2013 described compounds active as inhibitors of different EBOV strains in vitro and in vivo , namely amodiaquine and chloroquine in one study 8 , clomiphene and toremifene in another 9 . These active molecules were used as they have both in vitro and in vivo activity to build a common features pharmacophore with Discovery Studio 4.1 (Biovia, San Diego, CA) from 3D conformations of the molecules generated with the CAESAR algorithm.…”

“…In both cases over 300 hits were retrieved initially. The van der Waals surface of amodiaquine (which was more potent than chloroquine 8 ) was added to limit the number of hits retrieved 17– 19 .…”

“…Two recent studies utilized high-throughput screens of a subset of FDA approved drugs against different EBOV strains (Zaire and Sudan) in vitro and in vivo . These independent reports suggested the promise of the antimalarials amodiaquine and chloroquine in one study 8 , while the selective estrogen receptor modulators (SERMs) clomiphene and toremifene were active in another 9 . Chloroquine to date has not progressed beyond the mouse EBOV model used in these studies.…”