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

Mélissanne de Wispelaere, Guangyan Du, Katherine A. Donovan, Tinghu Zhang, Nicholas A. Eleuteri, Jingting C. Yuan, Joann Kalabathula, Radosław P. Nowak, Eric S. Fischer, Nathanael S. Gray and Priscilla L. Yang ()
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Mélissanne de Wispelaere: Harvard Medical School
Guangyan Du: Harvard Medical School
Katherine A. Donovan: Harvard Medical School
Tinghu Zhang: Harvard Medical School
Nicholas A. Eleuteri: Dana-Farber Cancer Institute
Jingting C. Yuan: Dana-Farber Cancer Institute
Joann Kalabathula: Dana-Farber Cancer Institute
Radosław P. Nowak: Harvard Medical School
Eric S. Fischer: Harvard Medical School
Nathanael S. Gray: Harvard Medical School
Priscilla L. Yang: Harvard Medical School

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11429-w

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