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

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

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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