Escape Mutations in NS4B Render Dengue Virus Insensitive to the Antiviral Activity of the Paracetamol Metabolite AM404

Antimicrob Agents Chemother. 2016 Mar 25;60(4):2554-7. doi: 10.1128/AAC.02462-15. Print 2016 Apr.

Abstract

Despite the enormous disease burden associated with dengue virus infections, a licensed antiviral drug is lacking. Here, we show that the paracetamol (acetaminophen) metabolite AM404 inhibits dengue virus replication. Moreover, we find that mutations in NS4B that were previously found to confer resistance to the antiviral compounds NITD-618 and SDM25N also render dengue virus insensitive to AM404. Our work provides further support for NS4B as a direct or indirect target for antiviral drug development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetaminophen / metabolism
  • Acetaminophen / pharmacology
  • Antiviral Agents / pharmacology*
  • Arachidonic Acids / metabolism
  • Arachidonic Acids / pharmacology*
  • Biotransformation
  • Dengue Virus / drug effects*
  • Dengue Virus / genetics
  • Dengue Virus / growth & development
  • Dengue Virus / metabolism
  • Drug Resistance, Multiple, Viral / genetics*
  • Gene Expression
  • Genes, Reporter
  • HeLa Cells
  • Humans
  • Luciferases / genetics
  • Luciferases / metabolism
  • Microbial Sensitivity Tests
  • Mutation*
  • Naltrexone / analogs & derivatives
  • Naltrexone / pharmacology
  • Ribavirin / pharmacology
  • Viral Nonstructural Proteins / genetics*
  • Viral Nonstructural Proteins / metabolism
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Arachidonic Acids
  • NS4B protein, flavivirus
  • SDM 25N
  • Viral Nonstructural Proteins
  • Acetaminophen
  • Ribavirin
  • Naltrexone
  • Luciferases
  • N-(4-hydroxyphenyl)arachidonylamide

Grants and funding

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.