Discovery of Tricyclic Derivative as Novel and Potent Respiratory Syncytial Virus Fusion Glycoprotein Inhibitor with an Improved Pharmacokinetic Profile.

Authors

Li'ao Zhang, Bao Xue, Mingkang 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

Published in

Journal of medicinal chemistry. Sep 11, 2025. Epub Sep 11, 2025.

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.

PMID:
40931704
Bibliographic data and abstract were imported from PubMed on 11 Sep 2025.

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