title: Escape Mutations in NS4B Render Dengue Virus Insensitive to the Antiviral Activity of the Paracetamol Metabolite AM404.
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.
authors: Department of Medical Microbiology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors: Koen W R
authors: KW
authors: van Cleef
authors: Department of Medical Microbiology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors: Gijs J
authors: GJ
authors: Overheul
authors: Department of Medical Microbiology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors: Michael C
authors: MC
authors: Thomassen
authors: Department of Medical Microbiology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors: Jenni M
authors: JM
authors: Marjakangas
authors: Department of Medical Microbiology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands ronald.vanrij@radboudumc.nl.
authors: Ronald P
authors: http://orcid.org/0000-0003-0221-4689
authors: RP
authors: van Rij
mesh_terms: D000082:Acetaminophen / Q000378:metabolism / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology*; D001711:Biotransformation; D003716:Dengue Virus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D024921:Drug Resistance, Multiple, Viral / Q000235:genetics*; D015870:Gene Expression; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D009154:Mutation; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D012254:Ribavirin / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000235:genetics* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D001095:Arachidonic Acids; C080107:NS4B protein, flavivirus; C568302:SDM 25N; D017361:Viral Nonstructural Proteins; D000082:Acetaminophen; D012254:Ribavirin; D009271:Naltrexone; D008156:Luciferases; C107594:N-(4-hydroxyphenyl)arachidonylamide