E-Poster with pre-recorded video presentation Lorne Infection and Immunity 2021

Identification of estrogen receptor modulators as inhibitors of flavivirus infection (#308)

Nicholas S Eyre 1 2 , Emily N Kirby 2 , Daniel R Anfiteatro 2 , Gustavo Bracho 3 , Alice G Russo 4 , Peter A White 4 , Amanda L Aloia 3 , Michael R Beard 2
  1. College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia
  2. Research Centre for Infectious Diseases, School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia
  3. Cell Screen SA (CeSSA), Flinders Centre for Innovation in Cancer, Flinders University , Bedford Park, SA, Australia
  4. School of Biotechnology and Biomolecular Sciences , UNSW, Sydney, NSW, Australia

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 amongst 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.

  1. Identification of Estrogen Receptor Modulators as Inhibitors of Flavivirus Infection Eyre, N. S., Kirby, E. N., Anfiteatro, D. R., Bracho, G., Russo, A. G., White, P. A., Aloia, A. L. & Beard, M. R. (2020) Antimicrobial Agents and Chemotherapy. 64, 8, 20 p., e00289.