# Monensin and salinomycin exhibit broad-spectrum antiviral activity against enteroviruses by disrupting lysosomal acidification

## TL;DR

Monensin and salinomycin, ionophore antibiotics, show broad antiviral effects against enteroviruses by disrupting acidic conditions in cells.

## Contribution

The study reveals that monensin and salinomycin inhibit enterovirus infection by neutralizing endolysosomal pH during viral entry.

## Key findings

- Monensin and salinomycin reduce EV71 infection in a dose-dependent manner with IC50 values of 0.25 μM and 1.49 μM, respectively.
- Both agents inhibit EV71 at the entry stage, independent of viral binding and internalization.
- They neutralize acidic endolysosomal pH and block viral maturation, showing broad-spectrum antiviral activity against multiple enterovirus serotypes.

## Abstract

Enteroviruses, which belong to the Picornaviridae family, are implicated in a variety of illnesses that range from mild to severe, with some infections potentially being life-threatening. Among these, Enterovirus 71 (EV71) is recognized as one of the most virulent members of the enterovirus genus. Currently, there are no effective treatments available for EV infections. Ionophore antibiotics are small, hydrophobic, and lipophilic molecules approved for use in veterinary medicine as anti-coccidial feed additives. Notably, ionophore antibiotics such as monensin (MON) and salinomycin (SAL) have shown antiviral activity against specific virus groups, although the modes of actions are not yet well understood. This study investigates the antiviral effects and mechanisms of MON and SAL against enteroviruses. Our findings reveal a dose-dependent reduction in EV71 infection, with 50% inhibitory concentrations of 0.25 μM for MON and 1.49 μM for SAL. Mechanistic investigations demonstrated that both agents primarily inhibit EV71 infection at the entry stage, independent of viral binding and internalization. Furthermore, these agents effectively neutralized low pH levels within endolysosomes, which was associated with a decrease in antiviral efficacy when acidic conditions were maintained in the medium. Additionally, both agents showed the ability to block viral maturation, which requires an acidic environment. The antiviral effects of MON and SAL were also observed against various serotypes of enteroviruses. In summary, MON and SAL exhibit antiviral efficacy by neutralizing endolysosomal pH during the viral entry process, suggesting a potential broad-spectrum antiviral strategy that could be applicable to other viruses with similar replication pathways.