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

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 resi...

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Published inAntimicrobial agents and chemotherapy Vol. 60; no. 4; pp. 2554 - 2557
Main Authors van Cleef, Koen W R, Overheul, Gijs J, Thomassen, Michael C, Marjakangas, Jenni M, van Rij, Ronald P
Format Journal Article
LanguageEnglish
Published United States American Society for Microbiology 01.04.2016
Subjects
Acetaminophen - metabolism
Acetaminophen - pharmacology
Antiviral Agents
Antiviral Agents - pharmacology
Arachidonic Acids
Arachidonic Acids - metabolism
Arachidonic Acids - pharmacology
Biotransformation
Dengue Virus
Dengue Virus - drug effects
Dengue Virus - genetics
Dengue Virus - growth & development
Dengue Virus - metabolism
Drug Resistance, Multiple, Viral
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
Viral Nonstructural Proteins - genetics
Viral Nonstructural Proteins - metabolism
Virus Replication - drug effects
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Summary: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.
Bibliography:Citation van Cleef KWR, Overheul GJ, Thomassen MC, Marjakangas JM, van Rij RP. 2016. Escape mutations in NS4B render dengue virus insensitive to the antiviral activity of the paracetamol metabolite AM404. Antimicrob Agents Chemother 60:2554–2557. doi:10.1128/AAC.02462-15.
Present address: Michael C. Thomassen, Department of Physiology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
ISSN:0066-4804
1098-6596
DOI:10.1128/AAC.02462-15