Nucleotide Substrate Specificity of Anti-Hepatitis C Virus Nucleoside Analogs for Human Mitochondrial RNA Polymerase

Antimicrob Agents Chemother. 2017 Jul 25;61(8):e00492-17. doi: 10.1128/AAC.00492-17. Print 2017 Aug.

Abstract

Nucleoside analog inhibitors (NAIs) are an important class of antiviral agents. Although highly effective, some NAIs with activity against hepatitis C virus (HCV) can cause toxicity, presumably due to off-target inhibition of host mitochondrial RNA polymerase (POLRMT). The in vitro nucleotide substrate specificity of POLRMT was studied in order to explore structure-activity relationships that can facilitate the identification of nontoxic NAIs. These findings have important implications for the development of all anti-RNA virus NAIs.

Keywords: antiviral agents; hepatitis C virus; toxicity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Amides / adverse effects
  • Amides / pharmacology
  • Antiviral Agents / adverse effects
  • Antiviral Agents / pharmacology*
  • Catalytic Domain / drug effects
  • DNA-Directed RNA Polymerases / genetics*
  • DNA-Directed RNA Polymerases / metabolism*
  • Hepacivirus / drug effects*
  • Hepatitis C / drug therapy*
  • Humans
  • Mitochondria / drug effects*
  • Mitochondria / genetics
  • Nucleosides / pharmacology
  • Phosphoric Acids / adverse effects
  • Phosphoric Acids / pharmacology
  • Sofosbuvir / adverse effects
  • Sofosbuvir / pharmacology
  • Structure-Activity Relationship
  • Substrate Specificity

Substances

  • Amides
  • Antiviral Agents
  • Nucleosides
  • Phosphoric Acids
  • phosphoramidic acid
  • DNA-Directed RNA Polymerases
  • POLRMT protein, human
  • Sofosbuvir