Genome-wide CRISPR screens identify CLC-2 as a drug target for anti-herpesvirus therapy:tackling herpesvirus drug resistance  

作　　者：Fayu Yang Nan Wei Shuo Cai Jing Liu Qingping Lan Hao Zhang Lu Shang Bo Zheng Mi Wang Yingchun Liu Lifang Zhang Chenzhong Fei Wu Tong Changlong Liu Ersheng Kuang Guangzhi Tong Feng Gu 

机构地区：[1]Shanghai Veterinary Research Institute,Chinese Academy of Agricultural Sciences,Shanghai 200241,China [2]Key Laboratory of Veterinary Chemical Drugs and Pharmaceutics,Ministry of Agriculture and Rural Affairs,Shanghai 200241,China [3]State Key Laboratory for Animal Disease Control and Prevention,College of Veterinary Medicine,Lanzhou University,Lanzhou Veterinary Research Institute,Chinese Academy of Agricultural Sciences,Lanzhou 730000,China [4]Institute of Human Virology,Zhongshan School of Medicine,Sun Yat-Sen University,Guangzhou 510080,China [5]School of Medicine,Tsinghua University,Beijing 100084,China

出　　处：《Science China(Life Sciences)》2025年第2期515-526,共12页中国科学(生命科学英文版)

基　　金：supported by the National Natural Science Foundation of China(32071443);China Postdoctoral Science Foundation(2023M731465);the Natural Science Foundation of Gansu province(23JRRA1134)。

摘　　要：The emergence of drug resistance to virus(i.e.,acyclovir(ACV)to herpesviruses)has been termed one of the common clinical issues,emphasizing the discovery of new antiviral agents.To address it,a genome-wide clustered regularly interspaced short palindromic repeats(CRISPR)screening was performed in mouse haploid embryonic stem cells infected with pseudorabies virus(PRV),anα-herpesvirus causing human and pig diseases.The results demonstrated that type 2 voltage-gated chloride channels(CLC-2)encoded by one of the identified genes,CLCN2,is a potential drug target for anti-herpesvirus therapy.CLC-2 inhibitors,omeprazole(OME)and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid(DIDS),can efficiently inhibit infection of multiple herpesviruses in cellulo(i.e.,PRV,HSV and EBV),and effectively treat murine herpes simplex encephalitis(HSE).Additionally,DIDS was found to inhibit HSV-1 replication by blocking the PI3K/Akt pathway.Most importantly,both DIDS and OME were able to inhibit ACV-resistant HSV-1 strain infection.The study's findings suggest that targeting host-cell factors such as CLC-2 may be a promising approach to tackling herpesvirus drug resistance.The discovery of CLC-2 as a potential drug target for anti-herpesvirus therapy provides a new direction for the development of novel antiviral agents.

关 键 词：HERPESVIRUSES CRISPR host-directed therapy CLC-2 DIDS 

分 类 号：S859[农业科学—临床兽医学]