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Development of Novel Anti-influenza Thiazolides with Relatively Broad-Spectrum Antiviral Potentials.
Zhao, Lei; Yan, Yunzheng; Dai, Qingsong; Li, Xingzhou; Xu, Ke; Zou, Gang; Yang, Keyu; Li, Wei; Guo, Xiaojia; Yang, Jingjing; Li, Yuexiang; Xia, Qing; Cao, Ruiyuan; Zhong, Wu.
Afiliação
  • Zhao L; National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, People's Republic of China.
  • Yan Y; National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, People's Republic of China.
  • Dai Q; National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, People's Republic of China.
  • Li X; National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, People's Republic of China.
  • Xu K; State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, People's Republic of China.
  • Zou G; Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, People's Republic of China.
  • Yang K; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, People's Republic of China.
  • Li W; National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, People's Republic of China.
  • Guo X; National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, People's Republic of China.
  • Yang J; National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, People's Republic of China.
  • Li Y; National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, People's Republic of China.
  • Xia Q; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, People's Republic of China.
  • Cao R; National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, People's Republic of China 21cc@163.com zhongwu@bmi.ac.cn.
  • Zhong W; National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, People's Republic of China 21cc@163.com zhongwu@bmi.ac.cn.
Article em En | MEDLINE | ID: mdl-32312780
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Orthomyxoviridae / Infecções por Orthomyxoviridae / Influenza Humana Limite: Humans Idioma: En Revista: Antimicrob Agents Chemother Ano de publicação: 2020 Tipo de documento: Article País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Orthomyxoviridae / Infecções por Orthomyxoviridae / Influenza Humana Limite: Humans Idioma: En Revista: Antimicrob Agents Chemother Ano de publicação: 2020 Tipo de documento: Article País de publicação: Estados Unidos