Identification of FDA-approved bifonazole as a SARS-CoV-2 blocking agent following a bioreporter drug screen.
Mol Ther
; 30(9): 2998-3016, 2022 09 07.
Article
en En
| MEDLINE
| ID: mdl-35526097
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).
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Antivirales
/
SARS-CoV-2
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Tratamiento Farmacológico de COVID-19
/
Imidazoles
Tipo de estudio:
Diagnostic_studies
Límite:
Animals
País como asunto:
America do norte
Idioma:
En
Año:
2022
Tipo del documento:
Article