2. Academic Validation
  3. Modular Biomimetic Strategy Enables Discovery and SAR Exploration of Oxime Macrocycles as Influenza A Virus (H1N1) Inhibitors

Modular Biomimetic Strategy Enables Discovery and SAR Exploration of Oxime Macrocycles as Influenza A Virus (H1N1) Inhibitors

  • J Med Chem. 2024 May 23;67(10):8201-8224. doi: 10.1021/acs.jmedchem.4c00319.
Dandan Xu 1 2 3,  Ying Gong 4 3,  Lianju Zhang 1 2 3,  Fu Xiao 5 3 6,  Xinran Wang 6,  Ji Qin 1 2 3,  Lin Tan 1 2 3,  Teng Yang 1 3,  Zeng Lin 1 2 3,  Zhongliang Xu 2 3,  Xiujuan Liu 1 2 3,  Fuling Xiao 4 3,  Feili Zhang 2 3,  Feng Tang 2 3,  Jianping Zuo 4 3 6,  Xiaomin Luo 5 3 6,  Wei Huang 1 2 3,  Li Yang 4 3,  Weibo Yang 1 2 3
Affiliations

Affiliations

  • 1 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  • 2 State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 4 Laboratory of Immunopharmacology, State key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 5 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 6 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
PMID: 38736187 DOI: 10.1021/acs.jmedchem.4c00319
Abstract

Although vaccination remains the prevalent prophylactic means for controlling Influenza A virus (IAV) infections, novel structural antivirus small-molecule drugs with new mechanisms of action for treating IAV are highly desirable. Herein, we describe a modular biomimetic strategy to expeditiously achieve a new class of macrocycles featuring oxime, which might target the hemagglutinin (HA)-mediated IAV entry into the host cells. SAR analysis revealed that the size and linker of the macrocycles play an important role in improving potency. Particularly, as a 14-membered macrocyclic oxime, 37 exhibited potent inhibitory activity against IAV H1N1 with an EC50 value of 23 nM and low cytotoxicity, which alleviated cytopathic effects and protected cell survival obviously after H1N1 Infection. Furthermore, 37 showed significant synergistic activity with neuraminidase inhibitor oseltamivir in vitro.

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