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

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.

• Authors: 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 66 Issue 1 Pg. 188-219 (01 12 2023) ISSN: 1520-4804 [Electronic] United States
• PMID: 36521178 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• laudanosoline
• Tetrahydroisoquinolines
• Antiviral Agents
• Endonucleases

Topics

• Animals
• Mice
• Humans
• Influenza, Human
• Orthomyxoviridae
• Tetrahydroisoquinolines (pharmacology)
• Antiviral Agents (pharmacology, metabolism)
• Endonucleases