FDA-Approved Selective Estrogen Receptor Modulators Inhibit Ebola Virus Infection

Abstract

Ebola viruses remain a substantial threat to both civilian and military populations as bioweapons, during sporadic outbreaks, and from the possibility of accidental importation from endemic regions by infected individuals. Currently, no approved therapeutics exist to treat or prevent infection by Ebola viruses. Therefore, we performed an in vitro screen of Food and Drug Administration (FDA)– and ex–US-approved drugs and selected molecular probes to identify drugs with antiviral activity against the type species Zaire ebolavirus (EBOV). From this screen, we identified a set of selective estrogen receptor modulators (SERMs), including clomiphene and toremifene, which act as potent inhibitors of EBOV infection. Anti-EBOV activity was confirmed for both of these SERMs in an in vivo mouse infection model. This anti-EBOV activity occurred even in the absence of detectable estrogen receptor expression, and both SERMs inhibited virus entry after internalization, suggesting that clomiphene and toremifene are not working through classical pathways associated with the estrogen receptor. Instead, the response appeared to be an off-target effect where the compounds interfere with a step late in viral entry and likely affect the triggering of fusion. These data support the screening of readily available approved drugs to identify therapeutics for the Ebola viruses and other infectious diseases. The SERM compounds described in this report are an immediately actionable class of approved drugs that can be repurposed for treatment of filovirus infections.

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 .…”

“…In summary, this study has built on the previous publications that identified four FDA approved compounds active against different strains of EBOV 8, 9 . Our pharmacophore model for SERMs and aminoquinolines suggests that these compounds share multiple chemical features based on their overlap to the four hydrophobic features and a hydrogen bond acceptor ( Figure 1E) and they may have a common mechanism or target.…”

“…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.…”

“…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.…”

“…The result that SERMs show lower scores for binding to VP35 is rationalized by the finding that ‘clomiphene and toremifene inhibit EBOV VLP entry with some specificity to GP’ 1 , and therefore does not probably inhibit VP35.‘Chloroquine to date has not progressed beyond the mouse EBOV model used in these studies.’ This statement is not clear, does it mean that the others have progressed beyond the mouse EBOV model?The first few compounds in Supplemental Table 2 should be part of the main manuscript as a table.Color coding of pharmacophore features should be in Fig 1 too (it comes earlier than Table 1, where it is described).The structures look better with a white background.A 3 Å RMSD for redocking a given ligand is quite high 2 . The authors should consider the use of other docking methods, as a comparison.…”