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

作　　者：Yi-hong Wan Wen-yu Wu Song-xin Guo Shi-jun He Xiao-dong Tang Xiao-yun Wu Kutty Selva Nandakumar Min Zou Lin Li Xiao-guang Chen Shu-wen Liu Xin-gang Yao 

机构地区：[1]State Key Laboratory of Organ Failure Research,Guangdong Provincial Key Laboratory of New Drug Screening,School of Pharmaceutical Sciences,Southern Medical University,Guangzhou 510515,China [2]State Key Laboratory of Ophthalmology,Zhongshan Ophthalmic Center,Sun Yat-sen University,Guangzhou 510060,China [3]School of Pharmacy,Guangdong Medical University,Zhanjiang 523808,China [4]School of Public Health,Southern Medical University,Guangzhou 510515,China [5]Center of Pharmacy,Nanhai Hospital,Southern Medical University,Foshan 510080,China [6]Center of Clinical Pharmacy,Nanfang Hospital,Southern Medical University,Guangzhou 510515,China

出　　处：《Acta Pharmacologica Sinica》2020年第5期706-718,共13页中国药理学报（英文版）

基　　金：The National Natural Science Foundation of China(81603118,81700854);the Pearl River Nova Program of Guangzhou(201806010119);the Natural Science Foundation(2017A030313717);the“New Drug Creation and Development”Major scientific and technological projects of Guangdong Province(2019B020202002)supported this work.

摘　　要：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±0.2μM.In the cell-based cytopathic effect(CPE)assay,mol-5 inhibited DENV2 infectivity with an EC50 value of 4.5±0.08μM.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(2.5–10μM).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.

关 键 词：Dengue virus antiviral agent RdRp inhibitor triazolo[15-a]pyrimidine derivative inflammation JAK/STAT signaling pathway 

分 类 号：R96[医药卫生—药理学]