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

  • J Med Chem. 2022 Dec 15. doi: 10.1021/acs.jmedchem.2c00857.
Yixian Liao  1 ,  Yilu Ye  2 ,  Mingjian Liu  1 ,  Zhihao Liu  1 ,  Jinshen Wang  2 ,  Baixi Li  1 ,  Lijian Huo  1 ,  Yilian Zhuang  1 ,  Liye Chen  1 ,  Jianxin Chen  3 ,  Yongfeng Gao  1 ,  Xiaoyun Ning  1 ,  Sumei Li  4 ,  Shuwen Liu  2  5 ,  Gaopeng Song  1
Affiliations
  • 1. Key Laboratory for Biobased Materials and Energy of Ministry of Education, College of Materials and Energy, South China Agricultural University, Guangzhou 510642, China.
  • 2. Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 3. Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, China.
  • 4. College of Basic Medicine and Public Hygiene, Jinan University, Guangzhou 510632, China.
  • 5. State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Southern Medical University, Guangzhou 510515, China.
PMID: 36521178 DOI: 10.1021/acs.jmedchem.2c00857
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.

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