TCM theory-inspired discovery of DNJ-flavonoid conjugates as broad-spectrum anti-SARS-CoV-2 agents by primarily targeting ER-associated glycoprotein folding process

IF 6 2区 医学 Q1 CHEMISTRY, MEDICINAL
Yan-Yun Liu , Zheng-Ao Li , Yu-Zheng Zhou , Sen-Lin Wang , Zong-Peng Chen , Si-Xu Liu , Peng Zhan , Ying-Jun Zhou , Zan-Xian Xia , Xu Deng
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引用次数: 0

Abstract

The global COVID-19 pandemic caused by SARS-CoV-2 has underscored the urgent need for the development of new broad-spectrum antivirals to combat its high mutation rate and the emerging variants. Host ER α-glucosidases I/II are promising host-targeted therapeutic targets for the development of broad-spectrum antivirals against viral strains that depend on ERQC for infectivity. Herein, we designed and synthesized a series of TCM theory-inspired DNJ-flavonoid conjugates as novel α-glucosidase inhibitors, which were screened against their in vitro antiviral activities in non-replicative SARS-CoV-2 pseudovirus (PsV) assay. Remarkably, DNJ-20 not only demonstrated remarkable inhibition activity against α-glucosidase and viral entry process, but also exerted potent and broad-spectrum anti-coronaviral activity against SARS-CoV-2 pseudovirus (PsV), several SARS-CoV-2 variants, as well as HCoV-229E and HCoV-OC43, with EC50 values up to 1.49 μM, which is more potent than the benchmark α-glucosidase inhibitor UV-4 (DNJ-3). Besides, it had no observable cytotoxicity in HeLa-ACE2, HEK-293T and Beas-2B cells. Therefore, TCM theory-inspired DNJ-flavonoid conjugates can be served as promising drug leads for pan-coronavirus therapeutic development to combat current and future coronavirus pandemics.

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来源期刊
CiteScore
11.70
自引率
9.00%
发文量
863
审稿时长
29 days
期刊介绍: The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.
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