Q63, a novel DENV2 RdRp non-nucleoside inhibitor, inhibited DENV2 replication and infection
| Autor: | Qiuhua Zhu, Xiaoguang Chen, Shengen Wu, Xingang Yao, Kutty Selva Nandakumar, Wenyu Wu, Shuwen Liu, Shijun He, Ning Sun, Jinan Wang, Yihong Wan, Guo Songxin |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
viruses Dengue virus Virus Replication medicine.disease_cause Antiviral Agents Genome Cell Line Viral Proteins 03 medical and health sciences chemistry.chemical_compound Aedes Cricetinae RNA polymerase medicine Animals STAT1 Quinazolinones Pharmacology biology lcsh:RM1-950 Dengue Virus RNA-Dependent RNA Polymerase ISG15 Virology RNA silencing lcsh:Therapeutics. Pharmacology 030104 developmental biology chemistry Infectious disease (medical specialty) biology.protein Molecular Medicine Phosphorylation |
| Zdroj: | Journal of Pharmacological Sciences, Vol 138, Iss 4, Pp 247-256 (2018) |
| ISSN: | 1347-8613 |
| DOI: | 10.1016/j.jphs.2018.06.012 |
| Popis: | Dengue virus (DENV) annually infects 400 million people worldwide. Unfortunately, there is lack of widely protective vaccine or drugs against DENV. The viral RNA-dependent RNA polymerase (RdRp) of NS5 protein is highly conserved among different DENV subtypes, thus presenting itself as an attractive target for drug design. In the current research, SPRi was performed to screen compounds against DENV2 RdRp and 5(1H)-Quinazolinone,2-(4-bromophenyl)-2,3,4,6,7,8-hexahydro-7,7-dimethyl-1,3-diphenyl (Q63) was successfully screened out with a KD of 0.9 μM. Then, ITC and molecular docking assay was performed to access the binding mechanism between Q63 and DENV2 RdRp. Meanwhile, Q63 also decreased the intermediate dsRNA production, which was the product of RdRp. Further the antiviral effects of Q63 were evaluated on mosquito C6/36 cells and mammalian BHK-21 cells. Q63 reduced CPE and cell toxicity effect after DENV2 infection on C6/36 and BHK-21 cells, with an EC50 of 2.08 μM. Time of addition assay revealed that Q63 affected the early genome RNA replication stage, including genome RNA replication. In addition, Q63 down-regulated STAT1 phosphorylation, ISG15 and ISG54 after DENV2 infection. In summary, Q63 was found to be a novel RdRp non-nucleoside inhibitor and a potential lead compound for coping with DENV infectious disease in the future. Keywords: RdRp inhibitor, Quinazolinone derivative, DENV2 infection |
| Databáze: | OpenAIRE |
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