PXD022453 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Small molecule endoplasmic reticulum proteostasis regulator acts as a broad-spectrum inhibitor of Dengue and Zika virus infections |
Description | 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 a new 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. 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. |
HostingRepository | PRIDE |
AnnounceDate | 2021-01-18 |
AnnouncementXML | Submission_2021-01-17_23:46:42.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Jonathan Davies |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | TMT6plex-126 reporter+balance reagent acylated residue; monohydroxylated residue; iodoacetamide derivatized residue |
Instrument | Q Exactive HF; Orbitrap Exploris 480 |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2020-11-10 04:02:48 | ID requested | |
⏵ 1 | 2021-01-17 23:46:43 | announced | |
Publication List
Almasy KM, Davies JP, Lisy SM, Tirgar R, Tran SC, Plate L, Small-molecule endoplasmic reticulum proteostasis regulator acts as a broad-spectrum inhibitor of dengue and Zika virus infections. Proc Natl Acad Sci U S A, 118(3):(2021) [pubmed] |
Keyword List
submitter keyword: ER proteostasis |
flavivirus |
Activating transcription factor 6 (ATF6) |
Contact List
Lars Plate |
contact affiliation | Departments of Chemistry and Biological Sciences, Vanderbilt University |
contact email | lars.plate@vanderbilt.edu |
lab head | |
Jonathan Davies |
contact affiliation | Vanderbilt University |
contact email | jonathan.p.davies@vanderbilt.edu |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD022453
- Label: PRIDE project
- Name: Small molecule endoplasmic reticulum proteostasis regulator acts as a broad-spectrum inhibitor of Dengue and Zika virus infections