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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 L1, Yan Y1, Dai Q1, Li X1, Xu K2, Zou G3, Yang K4, Li W1, Guo X1, Yang J1, Li Y1, Xia Q4, Cao R5, Zhong W5.
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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