Identification of FDA-approved bifonazole as a SARS-CoV-2 blocking agent following a bioreporter drug screen

Mol Ther. 2022 Sep 7;30(9):2998-3016. doi: 10.1016/j.ymthe.2022.04.025. Epub 2022 May 6.

Abstract

We established a split nanoluciferase complementation assay to rapidly screen for inhibitors that interfere with binding of the receptor binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein with its target receptor, angiotensin-converting enzyme 2 (ACE2). After a screen of 1,200 US Food and Drug Administration (FDA)-approved compounds, we identified bifonazole, an imidazole-based antifungal agent, as a competitive inhibitor of RBD-ACE2 binding. Mechanistically, bifonazole binds ACE2 around residue K353, which prevents association with the RBD, affecting entry and replication of spike-pseudotyped viruses as well as native SARS-CoV-2 and its variants of concern (VOCs). Intranasal administration of bifonazole reduces lethality in K18-hACE2 mice challenged with vesicular stomatitis virus (VSV)-spike by 40%, with a similar benefit after live SARS-CoV-2 challenge. Our screen identified an antiviral agent that is effective against SARS-CoV-2 and VOCs such as Omicron that employ the same receptor to infect cells and therefore has high potential to be repurposed to control, treat, or prevent coronavirus disease 2019 (COVID-19).

Keywords: COVID-19; SARS-CoV-2; bifonazole; drug discovery; high-throughput screening; nanoluciferase bioreporter.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2 / antagonists & inhibitors
  • Animals
  • Antiviral Agents* / pharmacology
  • COVID-19* / drug therapy
  • Imidazoles* / pharmacology
  • Mice
  • Protein Binding
  • SARS-CoV-2* / drug effects
  • Spike Glycoprotein, Coronavirus / chemistry
  • United States
  • United States Food and Drug Administration

Substances

  • Antiviral Agents
  • Imidazoles
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Angiotensin-Converting Enzyme 2
  • bifonazole