PXD067975

PXD067975 is an original dataset announced via ProteomeXchange.

Title	Integrated phenotypic screening and chemical proteomics identifies ETF1 ligands that modulate viral translation and replication
Description	Emerging and re-emerging viruses pose a significant threat to global health. Although direct-acting antivirals have shown success, their efficacy is limited by the rapid emergence of drug-resistant viral variants. Hence, there is an urgent need for additional broad spectrum antiviral therapeutic strategies. Here, we identify by phenotypic screening a set of stereochemically defined photoreactive small molecules (photo-stereoprobes) that stereoselectively suppress SARS-CoV-2 replication in human lung epithelial cells. Structure-activity relationship-guided chemical proteomics identified the eukaryotic translation termination factor 1 (ETF1) as a target of the photo-stereoprobes, and this interaction was recapitulated with recombinant purified ETF1. We found that the photo-stereoprobes modulate programmed ribosomal frameshifting mechanisms essential for SARS-CoV-2 infection without causing ETF1 degradation, thus distinguishing the photo-stereoprobes from other known ETF1-directed small molecules. We finally show that the photo-stereoprobes also inhibit the replication of additional viruses with non-canonical ribosomal frameshifting mechanisms. Our findings thus identify a mechanistically distinct class of ETF1 ligands that implicate host translation termination processes as a potential target for antiviral development.
HostingRepository	PRIDE
AnnounceDate	2026-01-30
AnnouncementXML	Submission_2026-01-29_16:47:27.995.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Arthur Kim
SpeciesList	scientific name: Mammarenavirus; NCBI TaxID: NCBITaxon:1653394; scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606; scientific name: Influenza A virus; NCBI TaxID: NCBITaxon:11320; scientific name: Alphavirus; NCBI TaxID: NCBITaxon:11019; scientific name: Severe acute respiratory syndrome coronavirus 2; NCBI TaxID: NCBITaxon:2697049;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2025-09-02 02:06:34	ID requested
⏵ 1	2026-01-29 16:47:28	announced

10.1073/pnas.2524108123;

Kim AS, Ma K, Reinhardt CJ, Lazar DC, Ogasawara D, Shaw TM, de la Torre JC, Bailey AL, Melillo B, Teijaro JR, Cravatt BF, Integrated phenotypic screening and chemical proteomics identifies ETF1 ligands that modulate viral translation and replication. Proc Natl Acad Sci U S A, 123(5):e2524108123(2026) [pubmed]

submitter keyword: ribosomal frameshifting, photo-stereoprobes,Activity-based profiling, virus, SARS-CoV-2

Benjamin F. Cravatt
contact affiliation	The Scripps Research Institute
contact email	cravatt@scripps.edu
lab head
Arthur Kim
contact affiliation	The Scripps Research Institute
contact email	akim@scripps.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD067975
     1. Label: PRIDE project
     2. Name: Integrated phenotypic screening and chemical proteomics identifies ETF1 ligands that modulate viral translation and replication