The emergence of SARS-CoV-2 and its variants have posed a significant threat to humankind in tackling the viral spread. Furthermore, currently repurposed drugs and frontline antiviral agents have failed to cure severe ongoing infections effectively. This insufficiency has fuelled research for potent and safe therapeutic agents to treat COVID-19. Nonetheless, various vaccine candidates have displayed a differential efficacy and need for repetitive dosing. The FDA-approved polyether ionophore veterinary antibiotic for treating coccidiosis has been repurposed for treating SARS-CoV-2 infection (as shown by both in vitro and in vivo studies) and other deadly human viruses. Based on selectivity index values, ionophores display therapeutic effects at sub-nanomolar concentrations and exhibit selective killing ability. They act on different viral targets (structural and non-structural proteins), host-cell components leading to SARS-CoV-2 inhibition, and their activity is further enhanced by Zn supplementation. This review summarizes the anti-SARS-CoV-2 potential and molecular viral targets of selective ionophores like monensin, salinomycin, maduramicin, CP-80,219, nanchangmycin, narasin, X-206 and valinomycin. Ionophore combinations with Zn are a new therapeutic strategy that warrants further investigation for possible human benefits.
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