Identification of Estrogen Receptor Modulators as Inhibitors of Flavivirus Infection

Nicholas S. Eyre, Emily N. Kirby, Daniel R. Anfiteatro, Gustavo Bracho, Alice G. Russo, Peter A. White, Amanda L. Aloia, Michael R. Beard

Research output: Contribution to journalArticle

Abstract

Flaviviruses such as Zika virus (ZIKV), dengue virus (DENV), and West Nile virus (WNV) are major global pathogens for which safe and effective antiviral therapies are not currently available. To identify antiviral small molecules with well-characterized safety and bioavailability profiles, we screened a library of 2,907 approved drugs and pharmacologically active compounds for inhibitors of ZIKV infection using a high-throughput cell-based immunofluorescence assay. Interestingly, estrogen receptor modulators raloxifene hydrochloride and quinestrol were among 15 compounds that significantly inhibited ZIKV infection in repeat screens. Subsequent validation studies revealed that these drugs effectively inhibit ZIKV, DENV, and WNV (Kunjin strain) infection at low micromolar concentrations with minimal cytotoxicity in Huh-7.5 hepatoma cells and HTR-8 placental trophoblast cells. Since these cells lack detectable expression of estrogen receptors-α and -β (ER-α and ER-β) and similar antiviral effects were observed in the context of subgenomic DENV and ZIKV replicons, these compounds appear to inhibit viral RNA replication in a manner that is independent of their known effects on estrogen receptor signaling. Taken together, quinestrol, raloxifene hydrochloride, and structurally related analogues warrant further investigation as potential therapeutics for treatment of flavivirus infections.

Original languageEnglish
Article numbere00289
Number of pages20
JournalAntimicrobial agents and chemotherapy
Volume64
Issue number8
Early online date22 Jul 2020
DOIs
Publication statusPublished - Aug 2020
Externally publishedYes

Keywords

  • antiviral
  • antiviral agents
  • dengue virus
  • estrogen receptor
  • flavivirus
  • high-throughput screening
  • West Nile virus
  • Zika virus

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