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

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 (g.towers@ucl.ac.uk) and David L. Selwood (d.selwood@ucl.ac.uk)
Additional contact information
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
Dara Annett: University College London
Riccardo Zenezini Chiozzi: University College London
Ann-Kathrin Reuschl: University College London
Morten L. Govasli: University College London
Ying Ying Tan: University College London
Lucy G. Thorne: University College London
Clare Jolly: University College London
Konstantinos Thalassinos: University College London
Alessio Ciulli: University of Dundee
Greg J. Towers: University College London
David L. Selwood: University College London

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56317-8

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