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

  • Signal Transduct Target Ther. 2024 Jun 10;9(1):144. doi: 10.1038/s41392-024-01858-5.
Qi Yang  #  1  2 ,  Bao Xue  #  1  3 ,  Fengjiang Liu  #  1  2 ,  Yongzhi Lu  #  1  4 ,  Jielin Tang  #  1  2 ,  Mengrong Yan  1  2 ,  Qiong Wu  1  4 ,  Ruyi Chen  1  2 ,  Anqi Zhou  5 ,  Lijie Liu  1  2 ,  Junjun Liu  1  2 ,  Changbin Qu  1 ,  Qingxin Wu  1  2 ,  Muqing Fu  6 ,  Jiayi Zhong  1  2 ,  Jianwei Dong  1  3 ,  Sijie Chen  5 ,  Fan Wang  5 ,  Yuan Zhou  1  3 ,  Jie Zheng  7  8 ,  Wei Peng  9  10 ,  Jinsai Shang  11  12 ,  Xinwen Chen  13  14
Affiliations
  • 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. GMU-GIBH 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.
  • 9. Guangzhou National Laboratory, Guangzhou, 510005, China. [email protected].
  • 10. State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, 511436, China. [email protected].
  • 11. Guangzhou National Laboratory, Guangzhou, 510005, China. [email protected].
  • 12. School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China. [email protected].
  • 13. Guangzhou National Laboratory, Guangzhou, 510005, China. [email protected].
  • 14. State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, 511436, China. [email protected].
  • # Contributed equally.
PMID: 38853183 DOI: 10.1038/s41392-024-01858-5
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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