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Inhibition of cellular entry of lymphocytic choriomeningitis virus by amphipathic DNA polymers.
The prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) represents a powerful experimental model for the study of the basic virology and pathogenesis of arenaviruses. In the present study, we used the LCMV model to evaluate the anti-viral potential of phosphorothioate oligonucleotides against arenaviruses. Our findings indicate that amphipathic DNA polymers (APs) are potent inhibitors of infection with a series of LCMV isolates with IC(50) in the low nanomolar range. APs target the surface glycoprotein (GP) of LCMV and block viral entry and cell-cell propagation of the virus, without affecting later steps in replication or release of progeny virus from infected cells. The anti-viral action of APs is sequence-independent but is critically dependent on their size and hydrophobicity. Mechanistically, we provide evidence that APs disrupt the interaction between LCMVGP and its cellular receptor, alpha-dystroglycan. Exposure of LCMV to APs does not affect the stability of the GP virion spike and has no effect on the conformation of a neutralizing antibody epitope, suggesting rather subtle changes in the conformation and/or conformational dynamics of the viral GP.
Animals, Antiviral Agents/pharmacology, Cell Line, Cercopithecus aethiops, Cricetinae, Dystroglycans/metabolism, Humans, Hydrophobic and Hydrophilic Interactions, Lymphocytic choriomeningitis virus/drug effects, Lymphocytic choriomeningitis virus/pathogenicity, Membrane Glycoproteins/metabolism, Phosphorothioate Oligonucleotides/pharmacology, Vero Cells, Virus Internalization/drug effects
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