Molecular Basis for the Selective Inhibition of Respiratory Syncytial Virus RNA Polymerase by 2'-Fluoro-4'-Chloromethyl-Cytidine Triphosphate

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Viral RNA polymerase complexes mediate all of the enzymatic functions required for genomic replication and transcription in RNA viruses. Because of their essential role in the virus life cycle, RNA polymerases are major molecular targets for antiviral therapies. Sofosbuvir and mericitabine are related compounds belonging to a class of drugs called nucleoside analogs that inhibit the RNA polymerase of hepatitis C virus (HCV), a positive-strand RNA virus, but have no effect on negative-strand RNA viruses. The mechanistic reason for this inactivity is unknown. The only nucleoside analog currently under clinical evaluation against respiratory syncytial virus (RSV), a negative-strand RNA virus, is ALS-8176. In this study, we present the detailed mechanism of action of ALS-8112, the parent molecule of ALS-8176. A multidisciplinary approach combining cellular, chemical, structural, and enzymatic methods was employed to demonstrate that the triphosphate form of ALS-8112 targets the RNA polymerase of RSV, but not of HCV. A series of molecules structurally related to ALS-8112 displayed dual RSV/HCV inhibition, whereas mericitabine only targeted HCV RNA polymerase. Understanding the molecular basis of nucleotide selectivity towards distant viral RNA polymerases could not only be used to repurpose existing drugs against new viral infections, but also to design novel molecules with broad antiviral spectrum.

Vyšlo v časopise: Molecular Basis for the Selective Inhibition of Respiratory Syncytial Virus RNA Polymerase by 2'-Fluoro-4'-Chloromethyl-Cytidine Triphosphate. PLoS Pathog 11(6): e32767. doi:10.1371/journal.ppat.1004995
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004995

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