Enteroviruses contain many significant human pathogens, including poliovirus, enterovirus 71, coxsackieviruses and rhinoviruses. Most enterovirus infections subside mild or asymptomatically, but may also result in severe morbidity and mortality. Here, we report on the mechanism of antiviral action of a small molecule, TP219, as an inhibitor of enterovirus morphogenesis. Morphogenesis represents an important stage at the end of the virus replication cycle and requires multiple steps, of which some are only poorly understood. Better understanding of this process holds much potential to facilitate the development of new therapies to combat enterovirus infections. We demonstrate that TP219 rapidly depletes intracellular glutathione (GSH) by covalently binding free GSH resulting in the inhibition of virus morphogenesis without affecting viral RNA replication. We discovered that GSH directly interacts with viral capsid precursors and mature virions and that this interaction is required for the formation of an assembly intermediate (pentameric particles) and consequently infectious progeny. Remarkably, enteroviruses that were capable of replicating in the absence of GSH contained a surface-exposed methionine at the protomeric interface. We propose that GSH is an essential and stabilizing host factor during morphogenesis and that this stabilization is a prerequisite for a functional encapsidation of progeny viral RNA.
Vyšlo v časopise: Binding of Glutathione to Enterovirus Capsids Is Essential for Virion Morphogenesis. PLoS Pathog 10(4): e32767. doi:10.1371/journal.ppat.1004039 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004039
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