2. Academic Validation
  3. Design and Synthesis of PAN Endonuclease Inhibitors through Spirocyclization Strategy against Influenza A Virus

Design and Synthesis of PAN Endonuclease Inhibitors through Spirocyclization Strategy against Influenza A Virus

  • J Med Chem. 2025 Jul 10;68(13):13393-13407. doi: 10.1021/acs.jmedchem.5c00042.
Shuangrong Liu 1,  Yuting Li 2 3,  Bo Peng 1,  Shaokai Ni 2,  Shuaiyi Wang 2,  Qi Zhu 2,  Haifeng Li 2,  Qian Yang 4,  Hui Zhang 1,  Peichen Pan 1,  Jiayi Lin 2,  Yongping Yu 1 5,  Zeli Zhang 4,  Yushen Du 2,  Wenteng Chen 1 5
Affiliations

Affiliations

  • 1 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
  • 2 Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China.
  • 3 Institute of Immunology, Department of Surgical Oncology of The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China.
  • 4 Zhejiang Key Laboratory of Multi-Omics in Infection and Immunity, Center for Infectious Disease Research, School of Medicine, Westlake University, Hangzhou, Zhejiang 310024, China.
  • 5 Jinhua Institute of Zhejiang University, Jinhua, Zhejiang 321299, China.
PMID: 40533885 DOI: 10.1021/acs.jmedchem.5c00042
Abstract

The PAN Endonuclease Inhibitor baloxavir marked a significant advancement in influenza treatment. Herein, we reported the development of PAN inhibitors through structural simplification of baloxavir̀s tricyclic system coupled with strategic incorporation of a spirocyclic architecture, which aims to construct a new metal-binding pharmacophore with distinct three-dimensional features. Lead 39-(S) was identified and exhibited nanomolar potency against Influenza Virus polymerase complexes (IC50 = 17.4 nM), which was mechanistically attributed to PAN Endonuclease inhibition. Furthermore, 39-(S) demonstrated robust Antiviral activities against multiple current and different Influenza Virus strains while showing minimal cytotoxicity in MDCK cells, ensuring an exceptional selectivity index of more than 2.4 × 105 during Antiviral treatment. Additionally, both 39-(S) and its prodrug 41 significantly suppressed viral replication in an A/WSN/33 infected mouse model with efficacy profiles remarkably comparable to those of baloxavir. Collectively, 39-(S) emerges as a potent PAN inhibitor with the potential for further development.

Figures
Products