Identification of N- and C-3-Modified Laudanosoline Derivatives as Novel Influenza PAN Endonuclease Inhibitors

作者：Liao, Yixian; Ye, Yilu; Liu, Mingjian; Liu, Zhihao; Wang, Jinshen; Li, Baixi; Huo, Lijian; Zhuang, Yilian; Chen, Liye; Chen, Jianxin; Gao, Yongfeng; Ning, Xiaoyun; Li, Sumei^*; Liu, Shuwen^*; Song, Gaopeng^*

来源：Journal of Medicinal Chemistry, 2023, 66(1): 188-219.

DOI：10.1021/acs.jmedchem.2c00857

• VIRUS POLYMERASE
• STRUCTURAL BASIS
• OSELTAMIVIR
• EVOLUTION
• DISCOVERY
• DESIGN

Influenza PAN inhibitors are of particular importance in current efforts to develop a new generation of antiviral drugs due to the growing emergence of highly pathogenic influenza viruses and the resistance to existing antiviral inhibitors. Herein, we design and synthesize a set of 1,3-cis-N-substituted-1,2,3,4-tetrahydroisoquinoline derivatives to enhance their potency by further exploiting the pockets 3 and 4 in the PAN endonuclease based on the hit D,L-laudanosoline. Particularly, the lead compound 35 exhibited potent and broad anti-influenza virus effects with EC50 values ranging from 0.43 to 1.12 mu M in vitro and good inhibitory activity in a mouse model. Mechanistic studies demonstrated that 35 could bind tightly to the PAN endonuclease of RNA-dependent RNA polymerase, thus blocking the viral replication to exert antiviral activity. Overall, our study might establish the importance of 1,2,3,4-tetrahydroisoquinoline-6,7-diol-based derivatives for the development of novel PAN inhibitors of influenza viruses.

• 单位
  南方医科大学; 华南农业大学