2. Academic Validation
  3. Macrocycle-based PROTACs selectively degrade cyclophilin A and inhibit HIV-1 and HCV

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

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. g.towers@ucl.ac.uk.
  • 9 Wolfson Institute for Biomedical Research, University College London, London, UK. d.selwood@ucl.ac.uk.
  • # 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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