PXD014346 is an
original dataset announced via ProteomeXchange.
Dataset Summary
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 |
Dataset History
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. |
Publication List
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] |
Keyword List
submitter keyword: hcv, telaprevir, PROTAC, thalidomide, ubiquitin, crl4 |
Contact List
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 | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD014346
- Label: PRIDE project
- Name: Small Molecule Degraders of the Hepatitis C Virus Protease Reduce Susceptibility to Resistance Mutations