Discovery of a Macrocyclic Influenza Cap-Dependent Endonuclease Inhibitor
Jiajie Feng, Fengying Guo, Peng Li, Jing Zhang, Kaixuan Jiang, Zhenzhen Zhu, Shanshan Yin, Xiaowan Lin, Fusen Lin, Fubiao Xiao, Xiaoxia Xue, Haiying He, Shuhui Chen
Abstract
Influenza viruses (IFVs) have caused several pandemics and have claimed numerous lives since their first record in the early 20th century. While the outbreak of COVID-19 seemed to expel influenza from the sight of people for a short period of time, it is not surprising that it will recirculate around the globe after the coronavirus has mutated into a less fatal variant. Baloxavir marboxil ( 1 ), the prodrug of baloxavir ( 2 ) and a cap-dependent endonuclease (CEN) inhibitor, were approved by the FDA for the first treatment in almost 20 years. Despite their high antiviral potency, drug-resistant variants have been observed in clinical trials. Herein, we report a novel CEN inhibitor 8 with a delicately designed macrocyclic scaffold that exhibits a significantly smaller shift of inhibitory activity toward baloxavir-resistant variants.