Antiviral effect of thiazolides relies on mitochondrial mild uncoupling

Abstract

Background: Viruses are dependent on cellular energy metabolism for their replication, the drug Nitazoxanide (Alinia) was shown to interfere with both. An effect of Alinia on cellular energy metabolism is the uncoupling of mitochondrial oxidative phosphorylation (OXPHOS). Our hypothesis was that uncoupling grounds the antiviral properties of Alinia. Methods: Alinia or an unrelated uncoupler were applied to a viral releasing cell line to obtain the same increasing levels of uncoupling hence identical interference with OXPHOS. Findings: Decrease in infectious viral particles release reflected the intensity of interference irrespective of the nature of the drug and was significant with modest deviation (≤25%) from normal. Interpretations: A mild interference on cellular energy metabolism impacts significantly on viral replication cycle. This would explain antiviral properties in vitro moreover antiviral action of Alinia is supported by clinical trials. Perspectives: Altogether this indicates that moderate interference with mitochondrial bioenergetics should be considered as a ground for a therapeutic effect. In addition, Alinia would constitute example for a safe therapeutical use of an uncoupler, which deserves consideration for a wider range of applications.

The FDA-approved drug nitazoxanide is a potent inhibitor of human seasonal coronaviruses acting at postentry level: effect on the viral spike glycoprotein

“…Because of the critical role of the spike protein in coronavirus assembly ( Fung and Liu, 2019 ; Santopolo et al, 2021a ), hampering S maturation may result in hindering progeny virus particle formation; however, we cannot exclude the existence of additional mechanisms that may contribute to the antiviral activity of thiazolides. Multiple mechanisms have in fact been implicated in the host-directed antiviral activity of nitazoxanide depending on the type of viral pathogen, including: interfering with the host cell energy metabolism and decreasing cellular ATP levels by mild uncoupling of mitochondrial oxidative phosphorylation (OXPHOS; Hammad et al, 2022 ; Rossignol et al, 2022b ), and regulating the redox state of infected cells ( Huang et al, 2023 ); induction of autophagy by inhibiting the Akt/mTOR/ULK1 signaling pathway in different types of cells ( Lam et al, 2012 ; Shou et al, 2020 ); induction of PKR activation and subsequent phosphorylation of eIF2-α ( Elazar et al, 2009 ; Ashiru et al, 2014 ); amplification of the host innate immune response, via an increase in RIG-I-like receptor activation, enhanced mitochondrial antiviral signaling protein and interferon regulatory factor 3 activities ( Jasenosky et al, 2019 ); induction or enhancement of interferon (IFN)-stimulated gene expression ( Gekonge et al, 2015 ; Petersen et al, 2016 ; Trabattoni et al, 2016 ; Jasenosky et al, 2019 ).…”

Nitazoxanide in the Treatment of COVID-19: A paradigm for Antiviral Drugs Targeting Host-Infected Cells

“…This effect on cellular ATP may account for several of the NTZ activities on viral proteins maturation and folding as well as the activation of AMPK and AMPK-dependent pathways, which has been established 10 . There is solid evidence for the impact of OXPHOS on cancer cell proliferation.…”