8KG5

Prefusion RSV F Bound to Lonafarnib and D25 Fab

Summary for 8KG5

• Entry DOI: 10.2210/pdb8kg5/pdb
• EMDB information: 37210
• Descriptor: Fusion glycoprotein F0,Fibritin, D25 heavy chain, D25 light chain, ... (4 entities in total)
• Functional Keywords: respiratory syncytial virus, f protein, lonafarnib, viral protein/immune system, viral protein-immune system complex
• Biological source: Human respiratory syncytial virus A (strain A2); More
• Total number of polymer chains: 5
• Total formula weight: 243338.77

Authors

Yang, Q.,Xue, B.,Liu, F.,Peng, W.,Chen, X. (deposition date: 2023-08-17, release date: 2024-06-19, Last modification date: 2024-10-23)

Primary citation

Yang, Q.,Xue, B.,Liu, F.,Lu, Y.,Tang, J.,Yan, M.,Wu, Q.,Chen, R.,Zhou, A.,Liu, L.,Liu, J.,Qu, C.,Wu, Q.,Fu, M.,Zhong, J.,Dong, J.,Chen, S.,Wang, F.,Zhou, Y.,Zheng, J.,Peng, W.,Shang, J.,Chen, X.
Farnesyltransferase inhibitor lonafarnib suppresses respiratory syncytial virus infection by blocking conformational change of fusion glycoprotein.
Signal Transduct Target Ther, 9:144-144, 2024

PubMed 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.

PubMed: 38853183
DOI: 10.1038/s41392-024-01858-5

Experimental method

ELECTRON MICROSCOPY (3.17 Å)