NS4B中的逃逸突变使登革热病毒对扑热息痛代谢物AM404的抗病毒活性不敏感。
Escape Mutations in NS4B Render Dengue Virus Insensitive to the Antiviral Activity of the Paracetamol Metabolite AM404.
作者信息
van Cleef Koen W R, Overheul Gijs J, Thomassen Michael C, Marjakangas Jenni M, van Rij Ronald P
机构信息
Department of Medical Microbiology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
Department of Medical Microbiology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
出版信息
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.
摘要
尽管登革热病毒感染带来了巨大的疾病负担，但目前仍缺乏经许可的抗病毒药物。在此，我们表明对乙酰氨基酚（扑热息痛）的代谢产物AM404可抑制登革热病毒复制。此外，我们发现，先前发现的对抗病毒化合物NITD-618和SDM25N具有抗性的NS4B突变，也会使登革热病毒对AM404不敏感。我们的工作为将NS4B作为抗病毒药物开发的直接或间接靶点提供了进一步的支持。
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本文引用的文献
1
Secondary structure and membrane topology of dengue virus NS4B N-terminal 125 amino acids.
Biochim Biophys Acta. 2015 Dec;1848(12):3150-7. doi: 10.1016/j.bbamem.2015.09.016. Epub 2015 Sep 25.
2
Discovery of Dengue Virus NS4B Inhibitors.
J Virol. 2015 Aug;89(16):8233-44. doi: 10.1128/JVI.00855-15.
3
HIV therapy-the state of art.
Curr Top Microbiol Immunol. 2015;389:1-29. doi: 10.1007/82_2015_440.
4
Targeting dengue virus NS4B protein for drug discovery.
Antiviral Res. 2015 Jun;118:39-45. doi: 10.1016/j.antiviral.2015.03.007. Epub 2015 Mar 19.
5
Hepatitis C.
Lancet. 2015 Mar 21;385(9973):1124-35. doi: 10.1016/S0140-6736(14)62401-6. Epub 2015 Feb 14.
6
AM404 inhibits NFAT and NF-κB signaling pathways and impairs migration and invasiveness of neuroblastoma cells.
Eur J Pharmacol. 2015 Jan 5;746:221-32. doi: 10.1016/j.ejphar.2014.11.023. Epub 2014 Nov 25.
7
Antiviral treatment of hepatitis C.
BMJ. 2014 Jul 7;348:g3308. doi: 10.1136/bmj.g3308.
8
The role of vector control in stopping the transmission of malaria: threats and opportunities.
Philos Trans R Soc Lond B Biol Sci. 2014 May 12;369(1645):20130431. doi: 10.1098/rstb.2013.0431. Print 2014.
9
Current progress in antiviral strategies.
Trends Pharmacol Sci. 2014 Feb;35(2):86-102. doi: 10.1016/j.tips.2013.11.006. Epub 2014 Jan 14.
10
Ten years of dengue drug discovery: progress and prospects.
Antiviral Res. 2013 Nov;100(2):500-19. doi: 10.1016/j.antiviral.2013.09.013. Epub 2013 Sep 27.
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