{"title":"法尼基转移酶抑制剂洛纳法尼通过阻断融合糖蛋白的构象变化抑制呼吸道合胞病毒感染。","authors":"Qi Yang, Bao Xue, Fengjiang Liu, Yongzhi Lu, Jielin Tang, Mengrong Yan, Qiong Wu, Ruyi Chen, Anqi Zhou, Lijie Liu, Junjun Liu, Changbin Qu, Qingxin Wu, Muqing Fu, Jiayi Zhong, Jianwei Dong, Sijie Chen, Fan Wang, Yuan Zhou, Jie Zheng, Wei Peng, Jinsai Shang, Xinwen Chen","doi":"10.1038/s41392-024-01858-5","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":40.8000,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11163014/pdf/","citationCount":"0","resultStr":"{\"title\":\"Farnesyltransferase inhibitor lonafarnib suppresses respiratory syncytial virus infection by blocking conformational change of fusion glycoprotein.\",\"authors\":\"Qi Yang, Bao Xue, Fengjiang Liu, Yongzhi Lu, Jielin Tang, Mengrong Yan, Qiong Wu, Ruyi Chen, Anqi Zhou, Lijie Liu, Junjun Liu, Changbin Qu, Qingxin Wu, Muqing Fu, Jiayi Zhong, Jianwei Dong, Sijie Chen, Fan Wang, Yuan Zhou, Jie Zheng, Wei Peng, Jinsai Shang, Xinwen Chen\",\"doi\":\"10.1038/s41392-024-01858-5\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":21766,\"journal\":{\"name\":\"Signal Transduction and Targeted Therapy\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":40.8000,\"publicationDate\":\"2024-06-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11163014/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Signal Transduction and Targeted Therapy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1038/s41392-024-01858-5\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Signal Transduction and Targeted Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41392-024-01858-5","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
呼吸道合胞病毒(RSV)是导致幼儿和老年人支气管炎和肺炎的主要原因。目前还没有获得批准的 RSV 特异性治疗小分子药物。通过高通量抗病毒筛选,我们发现了一种口服药物--前酰化抑制剂lonafarnib,它对RSV的融合过程有很强的抑制作用。Lonafarnib 对 RSV A 和 B 基因型都具有抗病毒活性,并且在 HEp-2 和人类原发性支气管上皮细胞(HBEC)中显示出较低的细胞毒性。添加时间和伪病毒试验表明,lonafarnib 可抑制 RSV 进入,但其抗病毒效力不依赖于法尼基转移酶。冷冻电镜显示,lonafarnib与RSV F可蜕变融合前构象中央空腔内的三重对称口袋结合。与诺那法尼相互作用的RSV F位点突变体对诺那法尼表现出抗药性,但对中和单克隆抗体帕利珠单抗仍完全敏感。此外,诺那法尼还能剂量依赖性地减少 RSV 在 BALB/c 小鼠体内的复制。总之,lonafarnib可能是一种潜在的RSV感染融合抑制剂。
Farnesyltransferase inhibitor lonafarnib suppresses respiratory syncytial virus infection by blocking conformational change of fusion glycoprotein.
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.
期刊介绍:
Signal Transduction and Targeted Therapy is an open access journal that focuses on timely publication of cutting-edge discoveries and advancements in basic science and clinical research related to signal transduction and targeted therapy.
Scope: The journal covers research on major human diseases, including, but not limited to:
Cancer,Cardiovascular diseases,Autoimmune diseases,Nervous system diseases.