PXD014346

PXD014346 is an original dataset announced via ProteomeXchange.

Title	Small Molecule Degraders of the Hepatitis C Virus Protease Reduce Susceptibility to Resistance Mutations
Description	Targeted protein degradation (TPD) has emerged as a promising new drug development paradigm. We leveraged this strategy to develop a new class of small molecule antivirals that induce proteasomal degradation of viral proteins. Telaprevir, a ‘reversible-covalent’ inhibitor that binds to the hepatitis C virus (HCV) protease active site was conjugated to ligands that recruit the CRL4CRBN ligase complex, yielding compounds that can both inhibit and induce the degradation of the HCV NS3/4A protease. We developed an optimized degrader, DGY-08-097, that potently inhibits HCV in a cellular infection model and demonstrate that protein degradation contributes to its antiviral activity. Finally, we show that this new class of antiviral agents can overcome viral variants that confer resistance to traditional enzymatic inhibitors such as telaprevir. Overall, our work provides proof-of-concept that targeted protein degradation may provide a new paradigm for the development of antivirals with superior resistance profiles.
HostingRepository	PRIDE
AnnounceDate	2019-07-03
AnnouncementXML	Submission_2019-08-12_07:33:28.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Eric Fischer
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2019-06-24 02:33:27	ID requested
1	2019-07-03 09:07:28	announced
⏵ 2	2019-08-12 07:33:30	announced	Updated publication reference for PubMed record(s): 31371704.

de Wispelaere M, Du G, Donovan KA, Zhang T, Eleuteri NA, Yuan JC, Kalabathula J, Nowak RP, Fischer ES, Gray NS, Yang PL, Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations. Nat Commun, 10(1):3468(2019) [pubmed]

submitter keyword: hcv, telaprevir, PROTAC, thalidomide, ubiquitin, crl4

Eric Fischer
contact affiliation	Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
contact email	eric_fischer@dfci.harvard.edu
lab head
Eric Fischer
contact affiliation	Dana-Farber Cancer Institute
contact email	eric_fischer@dfci.harvard.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2019/07/PXD014346

PRIDE project URI

• PRIDE
  1. PXD014346
     1. Label: PRIDE project
     2. Name: Small Molecule Degraders of the Hepatitis C Virus Protease Reduce Susceptibility to Resistance Mutations