Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations
Open accessAbstract
Targeted protein degradation is a promising drug development paradigm. Here we leverage 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 is conjugated to ligands that recruit the CRL4 CRBN ligase complex, yielding compounds that can both inhibit and induce the degradation of the HCV NS3/4A protease. An optimized degrader, DGY-08-097, potently inhibits HCV in a cellular infection model, and we 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.
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The feasibility of antiviral PROTACs was first established with the degradation of the hepatitis C virus NS3/4A protease in cell-based assays by an HCV inhibitor linked to CRBN.
“The feasibility of antiviral PROTACs was first established with the degradation of the hepatitis C virus (HCV) NS3/4A protease in cell-based assays by an HCV inhibitor linked to CRBN198”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [198]
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References 54 · Cited by 237
- Authors
- de Wispelaere, M., Du, G., Donovan, K. A., Zhang, T., Eleuteri, N. A., Yuan, J. C., Kalabathula, J., Nowak, R. P., Fischer, E. S., Gray, N. S., & Yang, P. L.
- Affiliations
- Harvard University (US)
- Dana-Farber Cancer Institute (US)
- Corresponding author
- Yang, Priscilla L.
- ORCID
- Venue
- Nature Communications
- Published
- 2019-08-01
- Volume
- 10
- Issue
- 1
- Pages
- 3468-3468
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6672008
- OpenAlex
- W2966441858
- Cited by
- 237
- References
- 54
- Citations by year
- 2026: 34 · 2025: 47 · 2024: 37 · 2023: 30 · 2022: 39 · 2021: 22 · 2020: 22 · 2019: 4 · 2014: 1
- FWCI
- 14.03
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Health & Human Services | NIH | NCI | Division of Cancer Epidemiology and Genetics, National Cancer Institute (R01 CA214608-02)
- U.S. Department of Health & Human Services | National Institutes of Health (U19AI109740)
- Dana-Farber Cancer Institute Medicinal Chemistry Core
- Quadrangle Fund for the Advancement and Seeding of Translational Research at Harvard Medical School
- Topics
- Health Sciences › Medicine › Hepatology › Hepatitis C virus research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- hepatitis C virus, HCV NS3/4A protease, targeted protein degradation, small-molecule degraders, telaprevir, proteasomal degradation, antiviral resistance, resistance mutations, covalent inhibitors
- MeSH terms
- Proof of Concept Study, Viral Proteases, Antiviral Agents, Hepatitis C, Humans, Ligands, Models, Molecular, Oligopeptides, Protease Inhibitors, Serine Endopeptidases, Drug Design, Hepacivirus, Viral Nonstructural Proteins, Drug Resistance, Viral, Nucleoside-Triphosphatase, Ubiquitin-Protein Ligases, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, DEAD-box RNA Helicases, Receptors, Interleukin-17, Gene Knockdown Techniques, HEK293 Cells, Proteolysis
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