Identification of N- and C-3-Modified Laudanosoline Derivatives as Novel Influenza PA<sub>N</sub> Endonuclease Inhibitors
Yixian Liao, Yilu Ye, Mingjian Liu, Zhihao Liu, Jinshen Wang, Baixi Li, Lijian Huo, Yilian Zhuang, Liye Chen, Jianxin Chen, Yongfeng Gao, Xiaoyun Ning, Sumei Li, Shuwen Liu, Gaopeng Song
Abstract
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 μM 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.