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  3. Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations

Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations

  • Nat Commun. 2019 Aug 1;10(1):3468. doi: 10.1038/s41467-019-11429-w.
Mélissanne de Wispelaere 1,  Guangyan Du 2 3,  Katherine A Donovan 2 3,  Tinghu Zhang 2 3,  Nicholas A Eleuteri 3,  Jingting C Yuan 3,  Joann Kalabathula 3,  Radosław P Nowak 2 3,  Eric S Fischer 2 3,  Nathanael S Gray 2 3,  Priscilla L Yang 4
Affiliations

Affiliations

  • 1 Department of Microbiology and Blavatnik Institute, Harvard Medical School, Boston, MA, 02115, USA.
  • 2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
  • 3 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • 4 Department of Microbiology and Blavatnik Institute, Harvard Medical School, Boston, MA, 02115, USA. priscilla_yang@hms.harvard.edu.
PMID: 31371704 DOI: 10.1038/s41467-019-11429-w
Abstract

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 CRL4CRBN 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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