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  2. Development of Novel Anti-influenza Thiazolides with Relatively Broad-Spectrum Antiviral Potentials

Development of Novel Anti-influenza Thiazolides with Relatively Broad-Spectrum Antiviral Potentials

  • Antimicrob Agents Chemother. 2020 Jun 23;64(7):e00222-20. doi: 10.1128/AAC.00222-20.
Lei Zhao 1 Yunzheng Yan 1 Qingsong Dai 1 Xingzhou Li 1 Ke Xu 2 Gang Zou 3 Keyu Yang 4 Wei Li 1 Xiaojia Guo 1 Jingjing Yang 1 Yuexiang Li 1 Qing Xia 4 Ruiyuan Cao 5 Wu Zhong 5
Affiliations

Affiliations

  • 1 National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, People's Republic of China.
  • 2 State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, People's Republic of China.
  • 3 Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, People's Republic of China.
  • 4 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, People's Republic of China.
  • 5 National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, People's Republic of China [email protected] [email protected].
Abstract

Seasonal and pandemic influenza causes 650,000 deaths annually in the world. The emergence of drug resistance to specific anti-influenza virus drugs such as oseltamivir and baloxavir marboxil highlights the urgency of novel anti-influenza chemical entity discovery. In this study, we report a series of novel thiazolides derived from an FDA-approved drug, nitazoxanide, with Antiviral activity against influenza and a broad range of viruses. The preferred candidates 4a and 4d showed significantly enhanced anti-influenza virus potentials, with 10-fold improvement compared to results with nitazoxanide, and were effective against a variety of Influenza Virus subtypes including oseltamivir-resistant strains. Notably, the combination using compounds 4a/4d and oseltamivir carboxylate or zanamivir displayed synergistic Antiviral effects against oseltamivir-resistant strains. Mode-of-action analysis demonstrated that compounds 4a/4d acted at the late phase of the viral Infection cycle through inhibiting viral RNA transcription and replication. Further experiments showed that treatment with compounds 4a/4d significantly inhibited Influenza Virus infection in human lung organoids, suggesting the druggability of the novel thiazolides. In-depth transcriptome analysis revealed a series of upregulated cellular genes that may contribute to the Antiviral activities of 4a/4d. Together, the results of our study indicated the direction to optimize nitazoxanide as an anti-influenza drug and discovered two candidates with novel structures, compounds 4a/4d, that have relatively broad-spectrum Antiviral potentials.

Keywords

antiviral; influenza virus; synergetic effects; thiazolides.

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