2. Academic Validation
  3. Design, synthesis, and biological evaluation of novel penindolone derivatives as potential inhibitors of hemagglutinin-mediated membrane fusion

Design, synthesis, and biological evaluation of novel penindolone derivatives as potential inhibitors of hemagglutinin-mediated membrane fusion

  • Eur J Med Chem. 2023 Oct 5;258:115615. doi: 10.1016/j.ejmech.2023.115615.
Bohan Li 1,  Lianghao Huang 1,  Jiaqi Lin 1,  Xiaoyao Ma 1,  Yanan Luo 1,  Wenrui Gai 1,  Yingqi Xie 1,  Tianjiao Zhu 1,  Wei Wang 2,  Dehai Li 3
Affiliations

Affiliations

  • 1 Key Laboratory of Marine Drugs Chinese Ministry of Education, School of Medicine and Pharmacy, Sanya Oceanographic Institute, Ocean University of China, Qingdao, Sanya, PR China.
  • 2 Key Laboratory of Marine Drugs Chinese Ministry of Education, School of Medicine and Pharmacy, Sanya Oceanographic Institute, Ocean University of China, Qingdao, Sanya, PR China; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao, PR China. Electronic address: wwwakin@ouc.edu.cn.
  • 3 Key Laboratory of Marine Drugs Chinese Ministry of Education, School of Medicine and Pharmacy, Sanya Oceanographic Institute, Ocean University of China, Qingdao, Sanya, PR China; Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao, PR China; Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology, Qingdao, 266237, PR China. Electronic address: dehaili@ouc.edu.cn.
PMID: 37413878 DOI: 10.1016/j.ejmech.2023.115615
Abstract

Development and design of anti-influenza drugs with novel mechanisms is of great significance to combat the ongoing threat of influenza A virus (IAV). Hemagglutinin (HA) is regarded as a potential target for the therapy of IAV. Our previous research led to the discovery of penindolone (PND), a new diclavatol indole adduct, as an HA targeting leading compound exhibited anti-IAV activity. To enhance the bioactivity and understand the structure-activity relationships (SARs), 65 PND derivatives were designed and synthesized, and the anti-IAV activities as well as the HA targeting effects were systematically investigated in this study. Among them, compound 5g possessed high affinity to HA and was more effective than PND in terms of inhibiting HA-mediated membrane fusion. Compound 5g may act on the trypsin cleavage site of HA to exhibit a strong inhibition on membrane fusion. In addition, oral administration of 5g can significantly reduce the pulmonary virus titer, attenuate the weight loss, and improve the survival of IAV-infected mice, superior to the effects of PND. These findings suggest that the HA inhibitor 5g has potential to be developed into a novel broad-spectrum anti-IAV agent in the future.

Keywords

Hemagglutinin; Membrane fusion; PND derivatives; Structure-activity relationships; influenza A virus.

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