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; David L. Selwood

doi:10.1038/s41467-025-56317-8

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 (Lead / Corresponding author), David L. Selwood (Lead / Corresponding author)

Centre for Targeted Protein Degradation

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Article number	1484
Number of pages	17
Journal	Nature Communications
Volume	16
Issue number	1
Early online date	10 Feb 2025
DOIs	https://doi.org/10.1038/s41467-025-56317-8
Publication status	E-pub ahead of print - 10 Feb 2025

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

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10.1038/s41467-025-56317-8Licence: CC BY

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Cite this

Newton, L. S., Gathmann, C., Ridewood, S., Smith, R. J., Wijaya, A. J., Hornsby, T. W., Morling, K. L., Annett, D., Chiozzi, R. Z., Reuschl, A. K., Govasli, M. L., Tan, Y. Y., Thorne, L. G., Jolly, C., Thalassinos, K., Ciulli, A., Towers, G. J., & Selwood, D. L. (2025). Macrocycle-based PROTACs selectively degrade cyclophilin A and inhibit HIV-1 and HCV. Nature Communications, 16(1), Article 1484. Advance online publication. https://doi.org/10.1038/s41467-025-56317-8

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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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Newton, LS, Gathmann, C, Ridewood, S, Smith, RJ, Wijaya, AJ, Hornsby, TW, Morling, KL, Annett, D, Chiozzi, RZ, Reuschl, AK, Govasli, ML, Tan, YY, Thorne, LG, Jolly, C, Thalassinos, K, Ciulli, A, Towers, GJ & Selwood, DL 2025, 'Macrocycle-based PROTACs selectively degrade cyclophilin A and inhibit HIV-1 and HCV', Nature Communications, vol. 16, no. 1, 1484. https://doi.org/10.1038/s41467-025-56317-8

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AU - Newton, Lydia S.

AU - Gathmann, Clara

AU - Ridewood, Sophie

AU - Smith, Robert J.

AU - Wijaya, Andre J.

AU - Hornsby, Thomas W.

AU - Morling, Kate L.

AU - Annett, Dara

AU - Chiozzi, Riccardo Zenezini

AU - Reuschl, Ann Kathrin

AU - Govasli, Morten L.

AU - Tan, Ying Ying

AU - Thorne, Lucy G.

AU - Jolly, Clare

AU - Thalassinos, Konstantinos

AU - Ciulli, Alessio

AU - Towers, Greg J.

AU - Selwood, David L.

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N2 - 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.

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

Abstract

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EUbOPEN: Enabling and Unlocking biology in the OPEN (Joint with Goethe University Frankfurt, University of Oxford, Karolinska Institute and 9 others)

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

Abstract

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

EUbOPEN: Enabling and Unlocking biology in the OPEN (Joint with Goethe University Frankfurt, University of Oxford, Karolinska Institute and 9 others)

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