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Macrocycle-based PROTACs selectively degrade cyclophilin A and inhibit HIV-1 and HCV

Author

Listed:
  • Lydia S. Newton

    (University College London)

  • Clara Gathmann

    (University College London)

  • Sophie Ridewood

    (University College London)

  • Robert J. Smith

    (University College London)

  • Andre J. Wijaya

    (University of Dundee)

  • Thomas W. Hornsby

    (University College London)

  • Kate L. Morling

    (University College London
    University College London)

  • Dara Annett

    (University College London)

  • Riccardo Zenezini Chiozzi

    (University College London)

  • Ann-Kathrin Reuschl

    (University College London)

  • Morten L. Govasli

    (University College London
    University of Bergen)

  • Ying Ying Tan

    (University College London)

  • Lucy G. Thorne

    (University College London
    Imperial College London)

  • Clare Jolly

    (University College London)

  • Konstantinos Thalassinos

    (University College London
    University College London)

  • Alessio Ciulli

    (University of Dundee)

  • Greg J. Towers

    (University College London)

  • David L. Selwood

    (University College London)

Abstract

Targeting host proteins that are crucial for viral replication offers a promising antiviral strategy. We have designed and characterised antiviral PROteolysis TArgeting Chimeras (PROTACs) targeting the human protein cyclophilin A (CypA), a host cofactor for unrelated viruses including human immunodeficiency virus (HIV) and hepatitis C virus (HCV). The PROTAC warheads are based on fully synthetic macrocycles derived from sanglifehrin A, which are structurally different from the classical Cyp inhibitor, cyclosporine A. Our Cyp-PROTACs decrease CypA levels in cell lines and primary human cells and have high specificity for CypA confirmed by proteomics experiments. Critically, CypA degradation facilitates improved antiviral activity against HIV-1 in primary human CD4+ T cells compared to the non-PROTAC parental inhibitor, at limiting inhibitor concentrations. Similarly, we observe antiviral activity against HCV replicon in a hepatoma cell line. We propose that CypA-targeting PROTACs inhibit viral replication potently and anticipate reduced evolution of viral resistance and broad efficacy against unrelated viruses. Furthermore, they provide powerful tools for probing cyclophilin biology.

Suggested Citation

  • Lydia S. Newton & Clara Gathmann & Sophie Ridewood & Robert J. Smith & Andre J. Wijaya & Thomas W. Hornsby & Kate L. Morling & Dara Annett & Riccardo Zenezini Chiozzi & Ann-Kathrin Reuschl & Morten L., 2025. "Macrocycle-based PROTACs selectively degrade cyclophilin A and inhibit HIV-1 and HCV," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56317-8
    DOI: 10.1038/s41467-025-56317-8
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    References listed on IDEAS

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    1. Thomas Pertel & Stéphane Hausmann & Damien Morger & Sara Züger & Jessica Guerra & Josefina Lascano & Christian Reinhard & Federico A. Santoni & Pradeep D. Uchil & Laurence Chatel & Aurélie Bisiaux & M, 2011. "TRIM5 is an innate immune sensor for the retrovirus capsid lattice," Nature, Nature, vol. 472(7343), pages 361-365, April.
    2. 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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