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Publications

Journal Article Epublish 1 citation

PubMed: 39929804 DOI: 10.1038/s41467-025-56317-8

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

Nat Commun 16(1):1484

Authors: 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 Govasli, Ying Ying Tan, Lucy G Thorne, Clare Jolly, Konstantinos Thalassinos, Alessio Ciulli, Greg J Towers, David L Selwood

Affiliations

  • Division of Infection and Immunity, University College London, London, UK.
  • Wolfson Institute for Biomedical Research, University College London, London, UK.
  • Centre for Targeted Protein Degradation, School of Life Sciences, University of Dundee, Dundee, UK.
  • Division of Infection and Immunity, University College London, London, UK. Wolfson Institute for Biomedical Research, University College London, London, UK.
  • University College London Mass Spectrometry Science Technology Platform, Division of Biosciences, University College London, London, UK.
  • Division of Infection and Immunity, University College London, London, UK. Department of Biomedicine, Centre for Cancer Biomarkers, University of Bergen, Bergen, Norway.
  • Department of Infectious Diseases, Imperial College London, London, UK.
  • Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London, UK.
  • Division of Infection and Immunity, University College London, London, UK.
  • Wolfson Institute for Biomedical Research, University College London, London, UK.

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.

MeSH

Cells, Hiv-1, Cyclophilin A, Biological Science Disciplines, Virus Replication, Cyclosporine, Cyclophilins, Hiv, Cell Line, Viruses, Antiviral Agents