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

Author

Listed:
  • Mélissanne de Wispelaere

    (Harvard Medical School)

  • Guangyan Du

    (Harvard Medical School
    Dana-Farber Cancer Institute)

  • Katherine A. Donovan

    (Harvard Medical School
    Dana-Farber Cancer Institute)

  • Tinghu Zhang

    (Harvard Medical School
    Dana-Farber Cancer Institute)

  • 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
    Dana-Farber Cancer Institute)

  • Eric S. Fischer

    (Harvard Medical School
    Dana-Farber Cancer Institute)

  • Nathanael S. Gray

    (Harvard Medical School
    Dana-Farber Cancer Institute)

  • Priscilla L. Yang

    (Harvard Medical School)

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.

Suggested Citation

  • 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 & P, 2019. "Small molecule degraders of the hepatitis C virus protease reduce susceptibility to resistance mutations," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11429-w
    DOI: 10.1038/s41467-019-11429-w
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    Cited by:

    1. Jianyuan Zhao & Jing Wang & Xu Pang & Zhenlong Liu & Quanjie Li & Dongrong Yi & Yongxin Zhang & Xiaomei Fang & Tao Zhang & Rui Zhou & Tao Zhang & Zhe Guo & Wancang Liu & Xiaoyu Li & Chen Liang & Tao D, 2022. "An anti-influenza A virus microbial metabolite acts by degrading viral endonuclease PA," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Han-Yuan Liu & Zhengnian Li & Theresia Reindl & Zhixiang He & Xueer Qiu & Ryan P. Golden & Katherine A. Donovan & Adam Bailey & Eric S. Fischer & Tinghu Zhang & Nathanael S. Gray & Priscilla L. Yang, 2024. "Broad-spectrum activity against mosquito-borne flaviviruses achieved by a targeted protein degradation mechanism," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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