[1,2,4]Triazolo[1,5-a]pyrimidine derivative (Mol-5) is a new NS5-RdRp inhibitor of DENV2 proliferation and DENV2-induced inflammation

Autor: Guo Songxin, Yihong Wan, Xingang Yao, Min Zou, Xiao-yun Wu, Kutty Selva Nandakumar, Xiaodong Tang, Xiaoguang Chen, Shuwen Liu, Shijun He, Wenyu Wu, Lin Li
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
medicine.drug_class
viruses
Microbial Sensitivity Tests
Dengue virus
Viral Nonstructural Proteins
medicine.disease_cause
Antiviral Agents
Article
antiviral agent
Dengue
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
RNA polymerase
Cricetinae
medicine
Animals
Pharmacology (medical)
Luciferase
[1
2
4]triazolo[1
5-a]pyrimidine derivative
Polymerase
Cells
Cultured
Cytopathic effect
Cell Proliferation
Pharmacology
Infectivity
JAK/STAT signaling pathway
Inflammation
biology
RNA
General Medicine
Dengue Virus
Surface Plasmon Resonance
Triazoles
RNA-Dependent RNA Polymerase
Virology
Recombinant Proteins
RdRp inhibitor
Molecular Docking Simulation
030104 developmental biology
Pyrimidines
chemistry
030220 oncology & carcinogenesis
biology.protein
Antiviral drug
Zdroj: Acta Pharmacologica Sinica
ISSN: 1745-7254
1671-4083
Popis: Dengue fever is an acute infectious disease caused by dengue virus (DENV) and transmitted by Aedes mosquitoes. There is no effective vaccine or antiviral drug available to date to prevent or treat dengue disease. Recently, RNA-dependent RNA polymerase (RdRp), a class of polymerases involved in the synthesis of complementary RNA strands using single-stranded RNA, has been proposed as a promising drug target. Hence, we screened new molecules against DENV RdRp using our previously constructed virtual screening method. Mol-5, [1,2,4]triazolo[1,5-a]pyrimidine derivative, was screened out from an antiviral compound library (~8000 molecules). Using biophysical methods, we confirmed the direct interactions between mol-5 and purified DENV RdRp protein. In luciferase assay, mol-5 inhibited NS5-RdRp activity with an IC50 value of 1.28 ± 0.2 μM. In the cell-based cytopathic effect (CPE) assay, mol-5 inhibited DENV2 infectivity with an EC50 value of 4.5 ± 0.08 μM. Mol-5 also potently inhibited DENV2 RNA replication as observed in immunofluorescence assay and qRT-PCR. Both the viral structural (E) and non-structural (NS1) proteins of DENV2 were dose-dependently decreased by treatment with mol-5 (2.5–10 μM). Mol-5 treatment suppressed DENV2-induced inflammation in host cells, but had no direct effect on host defense (JAK/STAT-signaling pathway). These results demonstrate that mol-5 could be a novel RdRp inhibitor amenable for further research and development.
Databáze: OpenAIRE
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