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

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) prote...

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Autores principales: de Wispelaere, Mélissanne, Du, Guangyan, Donovan, Katherine A., Zhang, Tinghu, Eleuteri, Nicholas A., Yuan, Jingting C., Kalabathula, Joann, Nowak, Radosław P., Fischer, Eric S., Gray, Nathanael S., Yang, Priscilla L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6672008/
https://www.ncbi.nlm.nih.gov/pubmed/31371704
http://dx.doi.org/10.1038/s41467-019-11429-w
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author de Wispelaere, Mélissanne
Du, Guangyan
Donovan, Katherine A.
Zhang, Tinghu
Eleuteri, Nicholas A.
Yuan, Jingting C.
Kalabathula, Joann
Nowak, Radosław P.
Fischer, Eric S.
Gray, Nathanael S.
Yang, Priscilla L.
author_facet de Wispelaere, Mélissanne
Du, Guangyan
Donovan, Katherine A.
Zhang, Tinghu
Eleuteri, Nicholas A.
Yuan, Jingting C.
Kalabathula, Joann
Nowak, Radosław P.
Fischer, Eric S.
Gray, Nathanael S.
Yang, Priscilla L.
author_sort de Wispelaere, Mélissanne
collection PubMed
description 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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spelling pubmed-66720082019-08-02 Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations de Wispelaere, Mélissanne Du, Guangyan Donovan, Katherine A. Zhang, Tinghu Eleuteri, Nicholas A. Yuan, Jingting C. Kalabathula, Joann Nowak, Radosław P. Fischer, Eric S. Gray, Nathanael S. Yang, Priscilla L. Nat Commun Article 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. Nature Publishing Group UK 2019-08-01 /pmc/articles/PMC6672008/ /pubmed/31371704 http://dx.doi.org/10.1038/s41467-019-11429-w Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
de Wispelaere, Mélissanne
Du, Guangyan
Donovan, Katherine A.
Zhang, Tinghu
Eleuteri, Nicholas A.
Yuan, Jingting C.
Kalabathula, Joann
Nowak, Radosław P.
Fischer, Eric S.
Gray, Nathanael S.
Yang, Priscilla L.
Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations
title Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations
title_full Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations
title_fullStr Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations
title_full_unstemmed Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations
title_short Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations
title_sort small molecule degraders of the hepatitis c virus protease reduce susceptibility to resistance mutations
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6672008/
https://www.ncbi.nlm.nih.gov/pubmed/31371704
http://dx.doi.org/10.1038/s41467-019-11429-w
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