Macrocycle-based PROTACs selectively degrade cyclophilin A and inhibit HIV-1 and HCV
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.
Authors
- Andre J. Wijaya (ORCID: https://orcid.org/0009-0006-0378-376X)
- Lydia S. Newton (ORCID: https://orcid.org/0009-0002-1706-8346)
- Konstantinos Thalassinos (ORCID: https://orcid.org/0000-0001-5072-8428)
- Morten L. Govasli
- David L. Selwood (ORCID: https://orcid.org/0000-0002-6817-5064)
- Lucy Thorne (ORCID: https://orcid.org/0000-0001-7358-6047)
- Robert J. Smith (ORCID: https://orcid.org/0000-0002-0003-7132)
- Alessio Ciulli (ORCID: https://orcid.org/0000-0002-8654-1670)
- Ying Ying Tan (ORCID: https://orcid.org/0000-0002-7452-606X)
- Riccardo Zenezini Chiozzi (ORCID: https://orcid.org/0000-0003-3904-5532)
- Greg J. Towers (ORCID: https://orcid.org/0000-0002-7707-0264)
- Ann‐Kathrin Reuschl (ORCID: https://orcid.org/0000-0002-1459-3519)
- Clara Gathmann (ORCID: https://orcid.org/0009-0002-9426-9774)
- Sophie Ridewood (ORCID: https://orcid.org/0000-0002-1845-361X)
- Clare Jolly (ORCID: https://orcid.org/0000-0002-4603-2281)
- Kate L. Morling (ORCID: https://orcid.org/0000-0002-2343-3410)
- Thomas W. Hornsby
- Dara Annett
Institutions
- University of Dundee (GB)
- Wolfson Foundation (GB)
- UK Dementia Research Institute (GB)
- Institute of Structural and Molecular Biology (GB)
- University of Bergen (NO)
- University College London (GB)
- Imperial College London (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-10
- DOI
- https://doi.org/10.1038/s41467-025-56317-8
- Citations
- 19
- Primary Topic
- Signaling Pathways in Disease
- Type
- article
- Field-Weighted Citation Impact
- 15.31
Funders
- Wellcome
- Wellcome Trust
- Multiple Sclerosis Society
- European Commission
- Rosetrees Trust
- Moorfields Eye Hospital NHS Foundation Trust
- Medical Research Council