2. Academic Validation
  3. Discovery of a spirocyclic influenza RNA-dependent RNA polymerase inhibitor

Discovery of a spirocyclic influenza RNA-dependent RNA polymerase inhibitor

  • Bioorg Chem. 2025 Nov:166:109109. doi: 10.1016/j.bioorg.2025.109109.
Jianxun He 1,  Zhaoxing Chu 2,  Qinlong Xu 2,  Yi Zou 3,  Gaofeng Lin 2,  Jiajia Mo 1,  Li Shao 4,  Yan Zhao 2,  Jiaming Li 5,  Wenfeng Ye 2,  Tao Fang 2,  Qihua Zhu 6,  Guangwei He 7,  Yungen Xu 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, China; Hefei Institute of Pharmaceutical Industry Co., Ltd., Hefei, 230088, China.
  • 2 Hefei Institute of Pharmaceutical Industry Co., Ltd., Hefei, 230088, China.
  • 3 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, China.
  • 4 Hefei Institute of Pharmaceutical Industry Co., Ltd., Hefei, 230088, China; College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China.
  • 5 College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China.
  • 6 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: zhuqihua@vip.126.com.
  • 7 Hefei Institute of Pharmaceutical Industry Co., Ltd., Hefei, 230088, China. Electronic address: hgwhipi@hotmail.com.
  • 8 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China; Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: xyg@cpu.edu.cn.
PMID: 41172783 DOI: 10.1016/j.bioorg.2025.109109
Abstract

The cap-dependent Endonuclease (CEN) inhibitor baloxavir marboxil (1) was approved by the FDA as a significant advancement in influenza treatment in nearly two decades. By expanding the tricyclic scaffold of baloxavir and introducing a spirocyclic architecture, a range of innovative compounds were designed and synthesized. Through iterative cycles of compound design and structure-activity relationship (SAR) analysis, guided by the cytopathic effect (CPE) assay, influenza polymerase inhibitory activity assay and molecular docking results, we hypothesized that the newly designed spirocyclic compounds could form a novel hydrogen-bonding interaction with the Tyr24 amino acid residue within the receptor binding pocket. Lead compound (S,S)-5a exhibited potent anti-influenza virus activity (EC50 = 3.76 nM), relatively low cytotoxicity (CC50 = 29.91 μM), and favorable liver microsomal stability. Moreover, both (S,S)-5a and its prodrug 6 effectively suppressed viral replication in a mouse model infected with A/WSN/33, demonstrating promising efficacy profiles. Both compound (S,S)-5a and its unique binding mode with the receptor warrant further investigation.

Keywords

CEN inhibitor; Influenza; Tyr24 amino acid residue; spirocyclic structure.

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