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

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.