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

Abstract

Despite significant breakthroughs in the discovery of direct-acting antivirals for several viruses, there is a need for improvement. Thus, drugs able to target host-infected cells may prove valuable in enhancing the efficacy of antivirals and avoiding resistance due to viral genetic changes. In this context, we summarize in this review the current knowledge on nitazoxanide's potential for treating COVID-19. Our review highlights nitazoxanide's very specific mode of action, targeting cellular energy through inhibiting mitochondrial oxidative phosphorylation (OXPHOS) and stimulating the innate immune response. Thus, nitazoxanide lowers the cellular ATP content and this leads to impaired viral replication and assembly. However, since nitazoxanide only yields a mild OXPHOS inhibition, this does not affect cell viability. Preclinical results and some clinical studies have suggested that nitazoxanide might be helpful for treating COVID-19. Indeed, some clinical studies have shown a decrease in severe COVID19 evolution as well as in viral multiplication; yet the results are still debated. Overall, the available information suggests the potential of nitazoxanide in association with direct-acting antivirals. In fact, this may hold true for other viruses than SARS-CoV-2 in the future. The impact of nitazoxanide on COVID-19 should be viewed as a paradigm for antiviral drugs targeting host-infected cells, and nitazoxanide should be part of the therapeutic tools for future emerging virus-related pandemics.