Farnesyltransferase inhibitor lonafarnib suppresses respiratory syncytial virus infection by blocking conformational change of fusion glycoprotein.
Signal Transduct Target Ther
; 9(1): 144, 2024 Jun 10.
Article
in 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyridines
/
Viral Fusion Proteins
/
Respiratory Syncytial Virus, Human
/
Respiratory Syncytial Virus Infections
Limits:
Animals
/
Humans
Language:
En
Journal:
Signal Transduct Target Ther
Year:
2024
Document type:
Article
Affiliation country:
China
Country of publication:
United kingdom