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-through...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.展开更多
基金supported by the Natural Science Foundation of Guangdong province(Grant no.2024A1515011589 to Q.Y.)the National Natural Science Foundation of China(Grant no.32000111 to Q.Y.,82170473 to J.S.)+3 种基金the Pearl River Talent Recruitment Program(Grant no.2019CX01Y422 to X.C.)the Guangzhou Laboratory(Grant no.SRPG22-002 to J.S.and X.C.,No.SRPG22-011 to W.P.and Q.Y.)the Basic and Applied Basic Research Projects of Guangzhou Basic Research Program(2023A04J0161 to Q.Y.,2021QN020451 to J.S.)the Young Elite Scientists Sponsorship Program by CAST(Grant no.2023QNRC001 to F.L.).
文摘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.
