Discovery of a Macrocyclic Influenza Cap-Dependent Endonuclease Inhibitor

  • J Med Chem. 2024 Feb 22;67(4):2570-2583. doi: 10.1021/acs.jmedchem.3c01715.
Jiajie Feng  1 ,  Fengying Guo  1 ,  Peng Li  1 ,  Jing Zhang  2 ,  Kaixuan Jiang  1 ,  Zhenzhen Zhu  1 ,  Shanshan Yin  1 ,  Xiaowan Lin  1 ,  Fusen Lin  1 ,  Fubiao Xiao  1 ,  Xiaoxia Xue  2 ,  Haiying He  1 ,  Shuhui Chen  1
Affiliations
  • 1. WuXi AppTec Co., Ltd., Shanghai 200131, China.
  • 2. Pharmaceutical Research Institute, Cisen Pharmaceutical Co., Ltd., Jining 272000, China.
PMID: 38301207 DOI: 10.1021/acs.jmedchem.3c01715
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.

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