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Broad-spectrum activity against mosquito-borne flaviviruses achieved by a targeted protein degradation mechanism

Author

Listed:
  • Han-Yuan Liu

    (Stanford University School of Medicine)

  • Zhengnian Li

    (Stanford University School of Medicine)

  • Theresia Reindl

    (Stanford University School of Medicine)

  • Zhixiang He

    (Dana-Farber Cancer Institute)

  • Xueer Qiu

    (University of Wisconsin–Madison)

  • Ryan P. Golden

    (Stanford University School of Medicine)

  • Katherine A. Donovan

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Adam Bailey

    (University of Wisconsin–Madison)

  • Eric S. Fischer

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Tinghu Zhang

    (Stanford University School of Medicine)

  • Nathanael S. Gray

    (Stanford University School of Medicine)

  • Priscilla L. Yang

    (Stanford University School of Medicine)

Abstract

Viral genetic diversity presents significant challenges in developing antivirals with broad-spectrum activity and high barriers to resistance. Here we report development of proteolysis targeting chimeras (PROTACs) targeting the dengue virus envelope (E) protein through coupling of known E fusion inhibitors to ligands of the CRL4CRBN E3 ubiquitin ligase. The resulting small molecules block viral entry through inhibition of E-mediated membrane fusion and interfere with viral particle production by depleting intracellular E in infected Huh 7.5 cells. This activity is retained in the presence of point mutations previously shown to confer partial resistance to the parental inhibitors due to decreased inhibitor-binding. The E PROTACs also exhibit broadened spectrum of activity compared to the parental E inhibitors against a panel of mosquito-borne flaviviruses. These findings encourage further exploration of targeted protein degradation as a differentiated and potentially advantageous modality for development of broad-spectrum direct-acting antivirals.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49161-9
    DOI: 10.1038/s41467-024-49161-9
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    References listed on IDEAS

    as
    1. 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.
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