Screening and identification of HTNV_(pv)entry inhibitors with high-throughput pseudovirus-based chemiluminescence  

作　　者：Xiaojing Wen Li Zhang Qiang Liu Xinyue Xiao Weijin Huang Youchun Wang 

机构地区：[1]Division of HIV/AIDS and Sex-transmitted Virus Vaccines,Institute for Biological Product Control,National Institutes for Food and Drug Control(NIFDC)and WHO Collaborating Center for Standardization and Evaluation of Biologicals,Beijing 102629,China [2]Department of Microbiological Laboratory Technology,School of Public Health,Shandong University,Jinan 250012,China [3]Institute for Reference Standards and Standardization,National Institutes for Food and Drug Control,Beijing 102629,China

出　　处：《Virologica Sinica》2022年第4期531-537,共7页中国病毒学（英文版）

基　　金：National Science and Technology Major Projects of Infectious Disease(grant number 2018ZX10731101)。

摘　　要：Hantaviruses,such as Hantaan virus(HTNV)and Seoul virus,are the causative agents of Hantavirus cardiopulmonary syndrome(HCPS)and hemorrhagic fever with renal syndrome(HFRS),and are important zoonotic pathogens.China has the highest incidence of HFRS,which is mainly caused by HTNV and Seoul virus.No approved antiviral drugs are available for these hantaviral diseases.Here,a chemiluminescence-based highthroughput-screening(HTS)assay was developed and used to screen HTNV pseudovirus(HTNVpv)inhibitors in a library of 1813 approved drugs and 556 small-molecule compounds from traditional Chinese medicine sources.We identified six compounds with in vitro anti-HTNVpvactivities in the low-micromolar range(EC50values of0.1–2.2μmol/L;selectivity index of 40–900).Among the six selected compounds,cepharanthine not only showed good anti-HTNVpvactivity in vitro but also inhibited HTNVpv-fluc infection in Balb/c mice 5 h after infection by94%(180 mg/kg/d,P<0.01),93%(90 mg/kg/d,P<0.01),or 92%(45 mg/kg/d,P<0.01),respectively,in a bioluminescent imaging mouse model.A time-of-addition analysis suggested that the antiviral mechanism of cepharanthine involves the membrane fusion and entry phases.Overall,we have established a HTS method for antiviral drugs screening,and shown that cepharanthine is a candidate for HCPS and HFRS therapy.These findings may offer a starting point for the treatment of patients infected with hantaviruses.

关 键 词：Hantaan virus(HTNV) High-throughput screening(HTS) INHIBITOR Drug repurposing 

分 类 号：R965.1[医药卫生—药理学]