Jornal de Doenças Infecciosas e Medicina Preventiva
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Mechanism of Antiviral Activity of Nitazoxanide: Effect on Adenosine Triphosphate in Influenza-Virus Infected Madin Darby Canine Kidney Cells

Jean-François Rossignol, Aloys SL Tijsma, Carel A van Baalen

Background: Nitazoxanide (NTZ), a broad-spectrum antiviral undergoing clinical development for treating influenza, COVID-19 and other viral respiratory illnesses, is a mild uncoupler of oxidative phosphorylation.

Methods: We evaluated the effect of Tizoxanide (TIZ), the active circulating metabolite of NTZ, on Adenosine Triphosphate (ATP) and cell viability in Madin-Darby Canine Kidney (MDCK) cells and in MDCK cells infected with influenza A and B viruses.

Results: TIZ decreased cellular ATP in a dose-dependent manner in MDCK cells and in MDCK cells infected with influenza A and B viruses. Maximum inhibition of ATP in influenza-infected or uninfected MDCK cells reached up to 45% after 6 and 24 hours of exposure to 100 μM TIZ. The decrease in cellular ATP did not affect cell viability and was reversible after eliminating TIZ from the culture. TIZ concentrations required to decrease cellular ATP levels were similar to those reported to inhibit replication of influenza A and B viruses.

Conclusion: The inhibitory effect of NTZ on replication of influenza and other respiratory viruses is related to its effect on host cell energy metabolism and downstream effects on cell signaling pathways. Modest and transient reductions of ATP do not affect viability of host cells but deny viruses’ access to energy and cellular machinery required for efficient replication.