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

文献类型：期刊论文

作者Yang, Qi7,8; Xue, Bao6,8; Liu, Fengjiang7,8; Lu, Yongzhi5,8; Tang, Jielin7,8; Yan, Mengrong7,8; Wu, Qiong5,8; Chen, Ruyi7,8; Zhou, Anqi4; Liu, Lijie7,8
刊名SIGNAL TRANSDUCTION AND TARGETED THERAPY
出版日期2024-06-10
卷号9期号:1页码:14
ISSN号2095-9907
DOI10.1038/s41392-024-01858-5
通讯作者Peng, Wei(peng_wei@gzlab.ac.cn) ; Shang, Jinsai(shang_jinsai@gzlab.ac.cn) ; Chen, Xinwen(chen_xinwen@gzlab.ac.cn)
英文摘要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.
WOS关键词STRUCTURAL-CHARACTERIZATION ; YOUNG-CHILDREN ; PROTEIN ; DISEASE ; IDENTIFICATION ; PREVENTION ; RSV ; VISUALIZATION ; PRENYLATION ; ACTIVATION
资助项目Guangzhou Laboratory (grant No.SRPG22-002) The Pearl River Talent Recruitment Program (grant No. 2019CX01Y422)[2024A1515011589] ; Natural Science Foundation of Guangdong province[32000111] ; Natural Science Foundation of Guangdong province[82170473] ; National Natural Science Foundation of China[2019CX01Y422] ; National Natural Science Foundation of China[SRPG22-002] ; National Natural Science Foundation of China[SRPG22-011] ; Pearl River Talent Recruitment Program[2023A04J0161] ; Pearl River Talent Recruitment Program[2021QN020451] ; Basic and Applied Basic Research Projects of Guangzhou Basic Research Program[2023QNRC001] ; Young Elite Scientists Sponsorship Program by CAST
WOS研究方向Biochemistry & Molecular Biology ; Cell Biology
语种英语
WOS记录号WOS:001242324000001
出版者SPRINGERNATURE
源URL[http://119.78.100.183/handle/2S10ELR8/311582]  
专题中国科学院上海药物研究所
通讯作者Peng, Wei; Shang, Jinsai; Chen, Xinwen
作者单位1.UCAS, Sch Pharmaceut Sci & Technol, Hangzhou lnstitute Adv Study, Hangzhou 310024, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
3.Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Guangzhou 510530, Peoples R China
4.Guangzhou Med Univ, GMU GIBH Joint Sch Life Sci, Guangzhou 511436, Peoples R China
5.Guangzhou Med Univ, Sch Basic Med Sci, Guangzhou 511436, Peoples R China
6.Chinese Acad Sci, Wuhan Inst Virol, Wuhan 430071, Peoples R China
7.Guangzhou Med Univ, State Key Lab Resp Dis, Guangzhou 511436, Peoples R China
8.Guangzhou Natl Lab, Guangzhou 510005, Peoples R China
推荐引用方式
GB/T 7714		 Yang, Qi,Xue, Bao,Liu, Fengjiang,et al. Farnesyltransferase inhibitor lonafarnib suppresses respiratory syncytial virus infection by blocking conformational change of fusion glycoprotein[J]. SIGNAL TRANSDUCTION AND TARGETED THERAPY,2024,9(1):14.
APA Yang, Qi.,Xue, Bao.,Liu, Fengjiang.,Lu, Yongzhi.,Tang, Jielin.,...&Chen, Xinwen.(2024).Farnesyltransferase inhibitor lonafarnib suppresses respiratory syncytial virus infection by blocking conformational change of fusion glycoprotein.SIGNAL TRANSDUCTION AND TARGETED THERAPY,9(1),14.
MLA Yang, Qi,et al."Farnesyltransferase inhibitor lonafarnib suppresses respiratory syncytial virus infection by blocking conformational change of fusion glycoprotein".SIGNAL TRANSDUCTION AND TARGETED THERAPY 9.1(2024):14.

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来源：上海药物研究所

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