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- Title
Farnesyltransferase inhibitor lonafarnib suppresses respiratory syncytial virus infection by blocking conformational change of fusion glycoprotein.
- Authors
Yang, Qi; Xue, Bao; Liu, Fengjiang; Lu, Yongzhi; Tang, Jielin; Yan, Mengrong; Wu, Qiong; Chen, Ruyi; Zhou, Anqi; Liu, Lijie; Liu, Junjun; Qu, Changbin; Wu, Qingxin; Fu, Muqing; Zhong, Jiayi; Dong, Jianwei; Chen, Sijie; Wang, Fan; Zhou, Yuan; Zheng, Jie
- Abstract
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.
- Publication
Signal Transduction & Targeted Therapy, 2024, Vol 9, Issue 1, p1
- ISSN
2095-9907
- Publication type
Article
- DOI
10.1038/s41392-024-01858-5