Year: 2025
Type: article
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.
Source: Nature Communications
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
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: G119964413, Institutional Strategic Support Fund, G2128189975, G3207356259, Studying lentiviruses to understand mechanisms, regulation and consequences of nucleic acid sensing, Permissivity and reprogramming during HIV-1 infection of T cells, G393177772, G434337789, G4691250445, G5702163051, What is special about pandemic HIV-1? How capsid cofactor interactions regulate DNA synthesis, innate immune detection and pandemic potential, Probing Druggability of Multisubunit Complexes: E3 Cullin RING Ligases, Institutional Strategic Support Fund, Expanding the proteomics and establishing top-down capabilities for the UCL Mass Spectrometry Science Technology Platform., DTP Bid Led by University College London, In vivo study of primary B cell responses, G7515806390, EUbOPEN: Enabling and Unlocking biology in the OPEN
OpenAlex ID: W4407338078