PXD022453

PXD022453 is an original dataset announced via ProteomeXchange.

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

Revision	Datetime	Status	ChangeLog Entry
0	2020-11-10 04:02:48	ID requested
⏵ 1	2021-01-17 23:46:43	announced

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]

submitter keyword: ER proteostasis

flavivirus

Activating transcription factor 6 (ATF6)

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

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PRIDE project URI

• PRIDE
  1. PXD022453
     1. Label: PRIDE project
     2. Name: Small molecule endoplasmic reticulum proteostasis regulator acts as a broad-spectrum inhibitor of Dengue and Zika virus infections