气候变化领域集成服务门户(CCPortal): Small-molecule endoplasmic reticulum proteostasis regulator acts as a broad-spectrum inhibitor of dengue and Zika virus infections

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DOI	10.1073/PNAS.2012209118
	Small-molecule endoplasmic reticulum proteostasis regulator acts as a broad-spectrum inhibitor of dengue and Zika virus infections
	Almasy K.M.; Davies J.P.; Lisy S.M.; Tirgar R.; Tran S.C.; Plate L.
发表日期	2021
ISSN	00278424
卷号	118 期号:3
英文摘要	Flaviviruses, including dengue and Zika, are widespread human pathogens; however, no broadly active therapeutics exist to fight infection. Recently, remodeling of endoplasmic reticulum (ER) proteostasis by pharmacologic regulators, such as compound 147, was shown to correct pathologic ER imbalances associated with protein misfolding diseases. Here, we establish an additional activity of compound 147 as an effective host-centered antiviral agent against flaviviruses. Compound 147 reduces infection by attenuating the infectivity of secreted virions without causing toxicity in host cells. Compound 147 is a preferential activator of the ATF6 pathway of the ER unfolded protein response, which requires targeting of cysteine residues primarily on protein disulfide isomerases (PDIs). We find that the antiviral activity of 147 is independent of ATF6 induction but does require modification of reactive thiols on protein targets. Targeting PDIs and additional non-PDI targets using RNAi and other small-molecule inhibitors was unable to recapitulate the antiviral effects, suggesting a unique polypharmacology may mediate the activity. Importantly, 147 can impair infection of multiple strains of dengue and Zika virus, indicating that it is suitable as a broad-spectrum antiviral agent. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Activating transcription factor 6 (ATF6); Antiviral; ER proteostasis; Flavivirus
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/181013
作者单位	Department of Chemistry, Vanderbilt University, Nashville, TN 37240, United States; Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN 37240, United States; Department of Biological Sciences, Vanderbilt University, Nashville, TN 37240, United States; Department of Biochemistry, Vanderbilt University, Nashville, TN 37240, United States; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37240, United States
推荐引用方式 GB/T 7714	Almasy K.M.,Davies J.P.,Lisy S.M.,et al. Small-molecule endoplasmic reticulum proteostasis regulator acts as a broad-spectrum inhibitor of dengue and Zika virus infections[J],2021,118(3).
APA	Almasy K.M.,Davies J.P.,Lisy S.M.,Tirgar R.,Tran S.C.,&Plate L..(2021).Small-molecule endoplasmic reticulum proteostasis regulator acts as a broad-spectrum inhibitor of dengue and Zika virus infections.Proceedings of the National Academy of Sciences of the United States of America,118(3).
MLA	Almasy K.M.,et al."Small-molecule endoplasmic reticulum proteostasis regulator acts as a broad-spectrum inhibitor of dengue and Zika virus infections".Proceedings of the National Academy of Sciences of the United States of America 118.3(2021).