tetano
Editor, Senior Moderator
Antimicrob Agents Chemother. 2020 Apr 20. pii: AAC.00222-20. doi: 10.1128/AAC.00222-20. [Epub ahead of print]
Development of Novel Anti-influenza Thiazolides with Relatively Broad-spectrum Antiviral Potentials.
Zhao L[SUP]1[/SUP], Yan Y[SUP]1[/SUP], Dai Q[SUP]1[/SUP], Li X[SUP]1[/SUP], Xu K[SUP]2[/SUP], Zou G[SUP]3[/SUP], Yang K[SUP]4[/SUP], Li W[SUP]1[/SUP], Guo X[SUP]1[/SUP], Yang J[SUP]1[/SUP], Li Y[SUP]1[/SUP], Xia Q[SUP]4[/SUP], Cao R[SUP]5[/SUP], Zhong W[SUP]5[/SUP].
Author information
Abstract
Seasonal and pandemic influenza causes 650,000 deaths annually in the world. The emergence of drug-resistance to specific anti-influenza 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 potentials with 10-fold improvement, compared with nitazoxanide, and were effective against a variety of influenza subtypes including oseltamivir-resistant strains. Notably, the combination using of compounds 4a/4d and oseltamivir carboxylate or zanamivir displayed synergistic antiviral effect against oseltamivir-resistant strain. Mode of action analysis demonstrated that compounds 4a/4d acted at the late phase of 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 up-regulated cellular genes that may contribute to the antiviral activities of 4a/4d Together, our study pointed the optimization direction of nitazoxanide as anti-influenza drug, and discovered two novel-structured candidates 4a/4d with relatively broad-spectrum antiviral potential.
Copyright ? 2020 American Society for Microbiology.
PMID:32312780DOI:10.1128/AAC.00222-20
Development of Novel Anti-influenza Thiazolides with Relatively Broad-spectrum Antiviral Potentials.
Zhao L[SUP]1[/SUP], Yan Y[SUP]1[/SUP], Dai Q[SUP]1[/SUP], Li X[SUP]1[/SUP], Xu K[SUP]2[/SUP], Zou G[SUP]3[/SUP], Yang K[SUP]4[/SUP], Li W[SUP]1[/SUP], Guo X[SUP]1[/SUP], Yang J[SUP]1[/SUP], Li Y[SUP]1[/SUP], Xia Q[SUP]4[/SUP], Cao R[SUP]5[/SUP], Zhong W[SUP]5[/SUP].
Author information
Abstract
Seasonal and pandemic influenza causes 650,000 deaths annually in the world. The emergence of drug-resistance to specific anti-influenza 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 potentials with 10-fold improvement, compared with nitazoxanide, and were effective against a variety of influenza subtypes including oseltamivir-resistant strains. Notably, the combination using of compounds 4a/4d and oseltamivir carboxylate or zanamivir displayed synergistic antiviral effect against oseltamivir-resistant strain. Mode of action analysis demonstrated that compounds 4a/4d acted at the late phase of 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 up-regulated cellular genes that may contribute to the antiviral activities of 4a/4d Together, our study pointed the optimization direction of nitazoxanide as anti-influenza drug, and discovered two novel-structured candidates 4a/4d with relatively broad-spectrum antiviral potential.
Copyright ? 2020 American Society for Microbiology.
PMID:32312780DOI:10.1128/AAC.00222-20