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Farnesyltransferase inhibitor lonafarnib suppresses respiratory syncytial virus infection by blocking conformational change of fusion glycoprotein.
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; Peng, Wei; Shang, Jinsai; Chen, Xinwen.
Afiliación
  • Yang Q; Guangzhou National Laboratory, Guangzhou, 510005, China.
  • Xue B; State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, 511436, China.
  • Liu F; Guangzhou National Laboratory, Guangzhou, 510005, China.
  • Lu Y; Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China.
  • Tang J; Guangzhou National Laboratory, Guangzhou, 510005, China.
  • Yan M; State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, 511436, China.
  • Wu Q; Guangzhou National Laboratory, Guangzhou, 510005, China.
  • Chen R; School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
  • Zhou A; Guangzhou National Laboratory, Guangzhou, 510005, China.
  • Liu L; State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, 511436, China.
  • Liu J; Guangzhou National Laboratory, Guangzhou, 510005, China.
  • Qu C; State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, 511436, China.
  • Wu Q; Guangzhou National Laboratory, Guangzhou, 510005, China.
  • Fu M; School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
  • Zhong J; Guangzhou National Laboratory, Guangzhou, 510005, China.
  • Dong J; State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, 511436, China.
  • Chen S; GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
  • Wang F; Guangzhou National Laboratory, Guangzhou, 510005, China.
  • Zhou Y; State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, 511436, China.
  • Zheng J; Guangzhou National Laboratory, Guangzhou, 510005, China.
  • Peng W; State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, 511436, China.
  • Shang J; Guangzhou National Laboratory, Guangzhou, 510005, China.
  • Chen X; Guangzhou National Laboratory, Guangzhou, 510005, China.
Signal Transduct Target Ther ; 9(1): 144, 2024 Jun 10.
Article en En | MEDLINE | ID: mdl-38853183
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piridinas / Proteínas Virales de Fusión / Virus Sincitial Respiratorio Humano / Infecciones por Virus Sincitial Respiratorio Límite: Animals / Humans Idioma: En Revista: Signal Transduct Target Ther Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piridinas / Proteínas Virales de Fusión / Virus Sincitial Respiratorio Humano / Infecciones por Virus Sincitial Respiratorio Límite: Animals / Humans Idioma: En Revista: Signal Transduct Target Ther Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido