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Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations
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Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations
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Journal Article
Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations
2019
Overview
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.
Targeted protein degradation (TPD) is a promising strategy for drug development. In this proof-of-concept study, the authors use telaprevir, which binds hepatitis C virus (HCV) NS3/4A protease, to target the protease for protein degradation, and show inhibition of wildtype as well as drug resistant HCV.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/31
/ 38/1
/ 38/35
/ 82/58
/ 82/80
/ Adaptor Proteins, Signal Transducing - genetics
/ Adaptor Proteins, Signal Transducing - metabolism
/ Antiviral Agents - chemistry
/ Antiviral Agents - pharmacology
/ Drug Resistance, Viral - drug effects
/ Drug Resistance, Viral - genetics
/ Humanities and Social Sciences
/ Humans
/ Intracellular Signaling Peptides and Proteins - antagonists & inhibitors
/ Intracellular Signaling Peptides and Proteins - metabolism
/ Ligands
/ Mutation
/ Oligopeptides - pharmacology
/ Protease
/ Protease Inhibitors - chemistry
/ Protease Inhibitors - pharmacology
/ Proteins
/ Science
/ Ubiquitin-Protein Ligases - metabolism
/ Viral Nonstructural Proteins - antagonists & inhibitors
/ Viral Nonstructural Proteins - metabolism
/ Viruses
