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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Cell Line, Tumor
  • Drug Design
  • Drug Resistance, Viral / drug effects*
  • Drug Resistance, Viral / genetics
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Hepacivirus / drug effects
  • Hepacivirus / metabolism
  • Hepatitis C / drug therapy
  • Hepatitis C / genetics
  • Hepatitis C / virology
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Ligands
  • Models, Molecular
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology
  • Proof of Concept Study
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Proteolysis / drug effects
  • Ubiquitin-Protein Ligases / metabolism
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Antiviral Agents
  • CRBN protein, human
  • IL17RB protein, human
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • NS3 protein, hepatitis C virus
  • NS4A cofactor peptide, Hepatitis C virus
  • Oligopeptides
  • Protease Inhibitors
  • Viral Nonstructural Proteins
  • telaprevir
  • Ubiquitin-Protein Ligases