Broad spectrum post-entry inhibitors of coronavirus replication: Cardiotonic steroids and monensin

Shahrzad Jahanshahi; Hong Ouyang; Choudhary Ahmed; Ali Zahedi Amiri; Subha Dahal; Yu-Qian Mao; David A J Van Ommen; Ramy Malty; Wenming Duan; Terek Been; Javier Hernandez; Maria Mangos; Jocelyn Nurtanto; Mohan Babu; Liliana Attisano; Walid A Houry; Theo J Moraes; Alan Cochrane

doi:10.1016/j.virol.2023.109915

Broad spectrum post-entry inhibitors of coronavirus replication: Cardiotonic steroids and monensin

Virology. 2024 Jan:589:109915. doi: 10.1016/j.virol.2023.109915. Epub 2023 Oct 31.

Authors

Shahrzad Jahanshahi¹, Hong Ouyang², Choudhary Ahmed³, Ali Zahedi Amiri³, Subha Dahal³, Yu-Qian Mao⁴, David A J Van Ommen⁴, Ramy Malty⁵, Wenming Duan², Terek Been³, Javier Hernandez⁶, Maria Mangos⁶, Jocelyn Nurtanto⁶, Mohan Babu⁷, Liliana Attisano⁸, Walid A Houry⁹, Theo J Moraes², Alan Cochrane¹⁰

Affiliations

¹ Dept. of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada; Dept. of Biochemistry, University of Toronto, Toronto, ON, Canada.
² Program in Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
³ Dept. of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
⁴ Dept. of Biochemistry, University of Toronto, Toronto, ON, Canada.
⁵ Dept. of Biochemistry, University of Toronto, Toronto, ON, Canada; Research and Innovation Centre, Department of Biochemistry, University of Regina, Regina, SK, Canada.
⁶ Donnelly Center, University of Toronto, Ontario, Canada.
⁷ Research and Innovation Centre, Department of Biochemistry, University of Regina, Regina, SK, Canada.
⁸ Dept. of Biochemistry, University of Toronto, Toronto, ON, Canada; Donnelly Center, University of Toronto, Ontario, Canada.
⁹ Dept. of Biochemistry, University of Toronto, Toronto, ON, Canada; Dept. of Chemistry, University of Toronto, Toronto, Ontario, Canada.
¹⁰ Dept. of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. Electronic address: cochrane@rogers.com.

PMID: 37931588
DOI: 10.1016/j.virol.2023.109915

Abstract

A small molecule screen identified several cardiotonic steroids (digitoxin and ouabain) and the ionophore monensin as potent inhibitors of HCoV-229E, HCoV-OC43, and SARS-CoV-2 replication with EC₅₀s in the low nM range. Subsequent tests confirmed antiviral activity in primary cell models including human nasal epithelial cells and lung organoids. Addition of digitoxin, ouabain, or monensin strongly reduced viral gene expression as measured by both viral protein and RNA accumulation. Furthermore, the compounds acted post virus entry. While the antiviral activity of digitoxin was dependent upon activation of the MEK and JNK signaling pathways but not signaling through GPCRs, the antiviral effect of monensin was reversed upon inhibition of several signaling pathways. Together, the data demonstrates the potent anti-coronavirus properties of two classes of FDA approved drugs that function by altering the properties of the infected cell, rendering it unable to support virus replication.

Keywords: Cardiotonic steroids; Coronavirus; Monensin; Pan antiviral.

MeSH terms

Antiviral Agents / pharmacology
Cardiac Glycosides* / pharmacology
Coronavirus 229E, Human*
Digitoxin / pharmacology
Humans
Monensin / pharmacology
Ouabain / pharmacology

Substances

Cardiac Glycosides
Monensin
Ouabain
Digitoxin
Antiviral Agents