Abstract
Enteroviruses (family of the Picornaviridae) cover a large group of medically important human pathogens for which no antiviral treatment is approved. Although these viruses have been extensively studied, some aspects of the viral life cycle, in particular morphogenesis, are yet poorly understood. We report the discovery of TP219 as a novel inhibitor of the replication of several enteroviruses, including coxsackievirus and poliovirus. We show that TP219 binds directly glutathione (GSH), thereby rapidly depleting intracellular GSH levels and that this interferes with virus morphogenesis without affecting viral RNA replication. The inhibitory effect on assembly was shown not to depend on an altered reducing environment. Using TP219, we show that GSH is an essential stabilizing cofactor during the transition of protomeric particles into pentameric particles. Sequential passaging of coxsackievirus B3 in the presence of low GSH-levels selected for GSH-independent mutants that harbored a surface-exposed methionine in VP1 at the interface between two protomers. In line with this observation, enteroviruses that already contained this surface-exposed methionine, such as EV71, did not rely on GSH for virus morphogenesis. Biochemical and microscopical analysis provided strong evidence for a direct interaction between GSH and wildtype VP1 and a role for this interaction in localizing assembly intermediates to replication sites. Consistently, the interaction between GSH and mutant VP1 was abolished resulting in a relocalization of the assembly intermediates to replication sites independent from GSH. This study thus reveals GSH as a novel stabilizing host factor essential for the production of infectious enterovirus progeny and provides new insights into the poorly understood process of morphogenesis.
Highlights
Enteroviruses, belonging to the family of the Picornaviridae, are non-enveloped, icosahedral viruses with a positive, single-stranded genome
We report on the mechanism of antiviral action of a small molecule, TP219, as an inhibitor of enterovirus morphogenesis
Better understanding of this process holds much potential to facilitate the development of new therapies to combat enterovirus infections
Summary
Enteroviruses, belonging to the family of the Picornaviridae, are non-enveloped, icosahedral viruses with a positive, single-stranded genome. Enteroviruses comprise many important pathogens of humans and animals. Most enterovirus infections subside asymptomatically or mildly, they can result in severe morbidity and even mortality. Polioviruses cause paralytic poliomyelitis; rhinovirus infections are associated with exacerbations of asthma and chronic obstructive pulmonary disease and enterovirus 71 may cause life-threatening encephalitis, in particular in Asia. Coxsackieviruses and echoviruses have been reported to cause acute clinical manifestations, including fulminant sepsis, aseptic meningitis and myocarditis [1]. Epidemiological studies strongly suggest a linkage between coxsackieviruses and the development of type 1 diabetes mellitus [2]. No drugs have been approved so far for the treatment or prophylaxis of enterovirus infections [3]
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