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Abstract
Vesicular stomatitis virus (VSV) represents a promising platform for developing oncolytic viruses, as well as vaccines against significant human pathogens. To safely control VSV infection in humans, small-molecule drugs that selectively inhibit VSV infection may be needed. Here, using a cell-based high-throughput screening assay followed by an in vitro transcription assay, compounds with a 7-hydroxy-6-methyl-3,4-dihydroquinolin-2(1H)-one structure and an aromatic group at position 4 (named vesiculopolins, VPIs) were identified as VSV RNA polymerase inhibitors. The most effective compound, VPI A, inhibited VSV-induced cytopathic effects and in vitro mRNA synthesis with micromolar to submicromolar 50% inhibitory concentrations. VPI A was found to inhibit terminal de novo initiation rather than elongation for leader RNA synthesis, but not mRNA capping, with the VSV L protein, suggesting that VPI A is targeted to the polymerase domain in the L protein. VPI A inhibited transcription of Chandipura virus, but not of human parainfluenza virus 3, suggesting that it specifically acts on vesiculoviral L proteins. These results suggest that VPIs may serve not only as molecular probes to elucidate the mechanisms of transcription of vesiculoviruses, but also as lead compounds to develop antiviral drugs against vesiculoviruses and other related rhabdoviruses.
Highlights
Vesicular stomatitis virus (VSV, an animal vesiculovirus belonging to the Rhabdoviridae family) has served as a paradigm for studying the molecular mechanisms of transcription and replication by nonsegmented negative strand RNA viruses (e.g., rabies virus (RABV), measles virus, Ebola virus)
VSV possesses a multifunctional RNA-dependent RNA polymerase (RdRp) L protein, which catalyzes all enzymatic reactions required for transcription and replication
VSV-induced cytopathic effects (CPEs), we performed screening of the ChemBridge library composed of 50,000 drug-like molecules
Summary
Vesicular stomatitis virus (VSV, an animal vesiculovirus belonging to the Rhabdoviridae family) has served as a paradigm for studying the molecular mechanisms of transcription and replication by nonsegmented negative strand RNA viruses (e.g., rabies virus (RABV), measles virus, Ebola virus). Genetic engineering of recombinant live-attenuated VSVs has significantly improved the safety of the VSV therapy [2,3,4,7], anti-VSV drugs may further decrease the risk of the potential side effects caused by VSV replication after cancer treatment or vaccination. Such drugs may be necessary, if unanticipated dissemination of live-attenuated VSV itself or its pathogenic revertant occurs in cancer patients and, immunocompromised individuals. VPI A showed a weak inhibitory activity against transcription by the L protein of CHPV, which is closely related to VSV and associated with acute encephalitis in children with high mortality rate [33,34]
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