Farnesyltransferase inhibitor lonafarnib suppresses respiratory syncytial virus infection by blocking conformational change of fusion glycoprotein  

作　　者：Qi Yang Bao Xue Fengjiang Liu Yongzhi Lu Jielin Tang Mengrong Yan Qiong Wu Ruyi Chen Anqi Zhou Lijie Liu Junjun Liu Changbin Qu Qingxin Wu Muqing Fu Jiayi Zhong Jianwei Dong Sijie Chen Fan Wang Yuan Zhou Jie Zheng Wei Peng Jinsai Shang Xinwen Chen 

机构地区：[1]Guangzhou National Laboratory,Guangzhou 510005,China [2]State Key Laboratory of Respiratory Disease,Guangzhou Medical University,Guangzhou 511436,China [3]Wuhan Institute of Virology,Chinese Academy of Sciences,Wuhan 430071,China [4]School of Basic Medical Sciences,Guangzhou Medical University,Guangzhou 511436,China [5]GMUGIBH Joint School of Life Sciences,Guangzhou Medical University,Guangzhou 511436,China [6]Guangzhou Institutes of Biomedicine and Health,Chinese Academy of Sciences,Guangzhou 510530,China [7]Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [8]School of Pharmaceutical Science and Technology,Hangzhou lnstitute for Advanced Study,UCAS,Hangzhou 310024,China

出　　处：《Signal Transduction and Targeted Therapy》2024年第7期2970-2983,共14页信号转导与靶向治疗（英文）

基　　金：supported by the Natural Science Foundation of Guangdong province(Grant no.2024A1515011589 to Q.Y.);the National Natural Science Foundation of China(Grant no.32000111 to Q.Y.,82170473 to J.S.);the Pearl River Talent Recruitment Program(Grant no.2019CX01Y422 to X.C.);the Guangzhou Laboratory(Grant no.SRPG22-002 to J.S.and X.C.,No.SRPG22-011 to W.P.and Q.Y.);the Basic and Applied Basic Research Projects of Guangzhou Basic Research Program(2023A04J0161 to Q.Y.,2021QN020451 to J.S.);the Young Elite Scientists Sponsorship Program by CAST(Grant no.2023QNRC001 to F.L.).

摘　　要：Respiratory syncytial virus(RSV)is the major cause of bronchiolitis and pneumonia in young children and the elderly.There are currently no approved RSV-specific therapeutic small molecules available.Using high-throughput antiviral screening,we identified an oral drug,the prenylation inhibitor lonafarnib,which showed potent inhibition of the RSV fusion process.Lonafarnib exhibited antiviral activity against both the RSV A and B genotypes and showed low cytotoxicity in HEp-2 and human primary bronchial epithelial cells(HBEC).Time-of-addition and pseudovirus assays demonstrated that lonafarnib inhibits RSV entry,but has farnesyltransferase-independent antiviral efficacy.Cryo-electron microscopy revealed that lonafarnib binds to a triple-symmetric pocket within the central cavity of the RSV F metastable pre-fusion conformation.Mutants at the RSV F sites interacting with lonafarnib showed resistance to lonafarnib but remained fully sensitive to the neutralizing monoclonal antibody palivizumab.Furthermore,lonafarnib dose-dependently reduced the replication of RSV in BALB/c mice.Collectively,lonafarnib could be a potential fusion inhibitor for RSV infection.

关 键 词：NEUTRAL METASTABLE approved 

分 类 号：R373.1[医药卫生—病原生物学]