title: Inhibition of viral RNA polymerases by nucleoside and nucleotide analogs: therapeutic applications against positive-strand RNA viruses beyond hepatitis C virus.
abstract: A number of important human infections are caused by positive-strand RNA viruses, yet almost none can be treated with small molecule antiviral therapeutics. One exception is the chronic infection caused by hepatitis C virus (HCV), against which new generations of potent inhibitors are being developed. One of the main molecular targets for anti-HCV drugs is the viral RNA-dependent RNA polymerase, NS5B. This review summarizes the search for nucleoside and nucleotide analogs that inhibit HCV NS5B, which led to the FDA approval of sofosbuvir in 2013. Advances in anti-HCV therapeutics have also stimulated efforts to develop nucleoside analogs against other positive-strand RNA viruses. Although it remains to be validated in the clinic, the prospect of using nucleoside analogs to treat acute infections caused by RNA viruses represents an important paradigm shift and a new frontier for future antiviral therapies.
authors.affiliation: Alios BioPharma, Inc., 260 East Grand Avenue, South San Francisco, CA 94080, USA. Electronic address: jdeval@aliosbiopharma.com.
authors.forename: Jerome
authors.initials: J
authors.lastname: Deval
authors.affiliation: Alios BioPharma, Inc., 260 East Grand Avenue, South San Francisco, CA 94080, USA.
authors.forename: Julian A
authors.initials: JA
authors.lastname: Symons
authors.affiliation: Alios BioPharma, Inc., 260 East Grand Avenue, South San Francisco, CA 94080, USA. Electronic address: lbeigelman@aliosbiopharma.com.
authors.forename: Leo
authors.initials: L
authors.lastname: Beigelman
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D009705:Nucleosides / Q000494:pharmacology* / Q000627:therapeutic use; D009711:Nucleotides / Q000494:pharmacology* / Q000627:therapeutic use; D012328:RNA Viruses / Q000187:drug effects* / Q000201:enzymology; D012367:RNA, Viral / Q000096:biosynthesis*; D000069474:Sofosbuvir; D014542:Uridine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D009705:Nucleosides; D009711:Nucleotides; D012367:RNA, Viral; D014542:Uridine Monophosphate; D012321:DNA-Directed RNA Polymerases; D000069474:Sofosbuvir