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

文献类型： 外文期刊

作者： Yang, Fayu 1 ; Wei, Nan 1 ; Cai, Shuo 1 ; Liu, Jing 1 ; Lan, Qingping 4 ; Zhang, Hao 1 ; Shang, Lu 1 ; Zheng, Bo 5 ; Wang, Mi 1 ; Liu, Yingchun 1 ; Zhang, Lifang 1 ; Fei, Chenzhong 1 ; Tong, Wu 1 ; Liu, Changlong 1 ; Kuang, Ersheng 4 ; Tong, Guangzhi 1 ; Gu, Feng 1 ;

作者机构： 1.Chinese Acad Agr Sci, Shanghai Vet Res Inst, Shanghai 200241, Peoples R China

2.Minist Agr & Rural Affairs, Key Lab Vet Chem Drugs & Pharmaceut, Shanghai 200241, Peoples R China

3.Lanzhou Univ, Lanzhou Vet Res Inst, State Key Lab Anim Dis Control & Prevent, Chinese Acad Agr Sci,Coll Vet Med, Lanzhou 730000, Peoples R China

4.Sun Yat Sen Univ, Inst Human Virol, Zhongshan Sch Med, Guangzhou 510080, Peoples R China

5.Tsinghua Univ, Sch Med, Beijing 100084, Peoples R China

关键词： herpesviruses; CRISPR; host-directed therapy; CLC-2; DIDS

期刊名称：SCIENCE CHINA-LIFE SCIENCES （ 影响因子：9.5； 五年影响因子：8.1 ）

ISSN： 1674-7305

年卷期： 2025 年 68 卷 2 期

页码：

收录情况： SCI

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), an alpha-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.

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