Discovery ofTricyclic Derivative as Novel and PotentRespiratory Syncytial Virus Fusion Glycoprotein Inhibitor with anImproved Pharmacokinetic Profile

作者：Li’ao Zhang, Bao Xue, Minghao Cao, Yuhan Mao, Feihai Ma, Limei Wang, Xiaolei Yang, Xinyi Zhao, Zhixia Qiu, Jielin Tang, Min Guo, Jinlei Bian, Xinwen Chen, Zhiyu Li, Xi Xu, Qi Yang · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.5c00692 · 被引用次数：4 · 研究领域：Respiratory viral infections research、Lung Cancer Research Studies、Pneumonia and Respiratory Infections

Abstract Respiratory syncytial virus (RSV) is a major pathogen causing acute respiratory infections, and the RSV fusion glycoprotein (F) has been identified as a key target for developing small-molecule inhibitors. Based on our prior identification of lonafarnib as an F protein inhibitor, medicinal chemistry efforts led to the development of CGR-51, which exhibits significantly enhanced potency against both laboratory and clinical RSV isolates in cellular assays. Time-of-addition and SPR assays indicate that CGR-51 inhibits viral entry by targeting the RSV F protein, but has farnesyltransferase-independent antiviral efficacy. Passage of RSV with CGR-51 selects for phenotypic resistance with the emergence of the K399N mutation in the RSV F protein. Additionally, CGR-51 exhibits an improved pharmacokinetic profile and effectively suppresses RSV replication in a BALB/c mouse model of RSV infection, while showing lower toxicity compared to lonafarnib. Collectively, CGR-51 represents a promising RSV F protein inhibitor candidate for the treatment of RSV infection.