Guangzhou National Laboratory, Guangzhou, 510005, China.
State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, 511436, China.
Signal Transduct Target Ther. 2024 Jun 10;9(1):144. doi: 10.1038/s41392-024-01858-5.
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.
呼吸道合胞病毒（RSV）是导致婴幼儿和老年人细支气管炎和肺炎的主要原因。目前尚无批准的 RSV 特异性治疗小分子可用。我们使用高通量抗病毒筛选方法，鉴定出一种名为 lonafarnib 的口服药物，它对 RSV 的融合过程具有很强的抑制作用。Lonafarnib 对 RSV A 和 B 基因型均表现出抗病毒活性，并且在 HEp-2 和人原代支气管上皮细胞（HBEC）中表现出低细胞毒性。添加时间和假病毒测定表明 lonafarnib 抑制 RSV 进入，但具有法尼基转移酶非依赖性的抗病毒功效。冷冻电镜显示 lonafarnib 结合到 RSV F 亚稳定预融合构象中央腔中的三重对称口袋中。与 lonafarnib 相互作用的 RSV F 位点突变体对 lonafarnib 表现出耐药性，但对中和单克隆抗体 palivizumab 仍完全敏感。此外，Lonafarnib 可剂量依赖性降低 BALB/c 小鼠中 RSV 的复制。总的来说，Lonafarnib 可能是 RSV 感染的潜在融合抑制剂。
