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

  • Nat Commun. 2025 Feb 10;16(1):1484. doi: 10.1038/s41467-025-56317-8.
Lydia S Newton  #  1 ,  Clara Gathmann  #  2 ,  Sophie Ridewood  1 ,  Robert J Smith  2 ,  Andre J Wijaya  3 ,  Thomas W Hornsby  2 ,  Kate L Morling  1  2 ,  Dara Annett  1 ,  Riccardo Zenezini Chiozzi  4 ,  Ann-Kathrin Reuschl  1 ,  Morten L Govasli  1  5 ,  Ying Ying Tan  1 ,  Lucy G Thorne  1  6 ,  Clare Jolly  1 ,  Konstantinos Thalassinos  4  7 ,  Alessio Ciulli  3 ,  Greg J Towers  8 ,  David L Selwood  9
Affiliations
  • 1. Division of Infection and Immunity, University College London, London, UK.
  • 2. Wolfson Institute for Biomedical Research, University College London, London, UK.
  • 3. Centre for Targeted Protein Degradation, School of Life Sciences, University of Dundee, Dundee, UK.
  • 4. University College London Mass Spectrometry Science Technology Platform, Division of Biosciences, University College London, London, UK.
  • 5. Department of Biomedicine, Centre for Cancer Biomarkers, University of Bergen, Bergen, Norway.
  • 6. Department of Infectious Diseases, Imperial College London, London, UK.
  • 7. Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London, UK.
  • 8. Division of Infection and Immunity, University College London, London, UK. [email protected].
  • 9. Wolfson Institute for Biomedical Research, University College London, London, UK. [email protected].
  • # Contributed equally.
PMID: 39929804 DOI: 10.1038/s41467-025-56317-8
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.

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