{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T02:49:23Z","timestamp":1777603763819,"version":"3.51.4"},"reference-count":60,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,6,11]],"date-time":"2024-06-11T00:00:00Z","timestamp":1718064000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Bundesministerium f\u00fcr Bildung und Forschung (BMBF)","award":["03Z22E511"],"award-info":[{"award-number":["03Z22E511"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Cyclophilin A (CypA), the cellular receptor of the immunosuppressant cyclosporin A (CsA), is an abundant cytosolic protein and is involved in a variety of diseases. For example, CypA supports cancer proliferation and mediates viral infections, such as the human immunodeficiency virus 1 (HIV-1). Here, we present the design of PROTAC (proteolysis targeting chimera) compounds against CypA to induce its intracellular proteolysis and to investigate their effect on immune cells. Interestingly, upon connecting to E3 ligase ligands, both peptide-based low-affinity binders and CsA-based high-affinity binders can degrade CypA at nM concentration in HeLa cells and fibroblast cells. As the immunosuppressive effect of CsA is not directly associated with the binding of CsA to CypA but the inhibition of phosphatase calcineurin by the CypA:CsA complex, we investigated whether a CsA-based PROTAC compound could induce CypA degradation without affecting the activation of immune cells. P3, the most efficient PROTAC compound discovered from this study, could deplete CypA in lymphocytes without affecting cell proliferation and cytokine production. This work demonstrates the feasibility of the PROTAC approach in depleting the abundant cellular protein CypA at low drug dosage without affecting immune cells, allowing us to investigate the potential therapeutic effects associated with the endogenous protein in the future.<\/jats:p>","DOI":"10.3390\/molecules29122779","type":"journal-article","created":{"date-parts":[[2024,6,11]],"date-time":"2024-06-11T11:58:58Z","timestamp":1718107138000},"page":"2779","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Cyclosporin A-Based PROTACs Can Deplete Abundant Cellular Cyclophilin A without Suppressing T Cell Activation"],"prefix":"10.3390","volume":"29","author":[{"given":"Katharina","family":"Hilbig","sequence":"first","affiliation":[{"name":"B CUBE Center for Molecular Bioengineering, Technische Universit\u00e4t Dresden, Tatzberg 41, 01307 Dresden, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Russell","family":"Towers","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital Carl Gustav Carus, 01307 Dresden, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc","family":"Schmitz","sequence":"additional","affiliation":[{"name":"German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"},{"name":"National Center for Tumor Diseases (NCT), 01307 Dresden, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Bornh\u00e4user","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital Carl Gustav Carus, 01307 Dresden, Germany"},{"name":"German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"},{"name":"National Center for Tumor Diseases (NCT), 01307 Dresden, Germany"},{"name":"School of Cancer and Pharmaceutical Science, King\u2019s College, London WC2R 2LS, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petra","family":"Lennig","sequence":"additional","affiliation":[{"name":"B CUBE Center for Molecular Bioengineering, Technische Universit\u00e4t Dresden, Tatzberg 41, 01307 Dresden, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6669-4995","authenticated-orcid":false,"given":"Yixin","family":"Zhang","sequence":"additional","affiliation":[{"name":"B CUBE Center for Molecular Bioengineering, Technische Universit\u00e4t Dresden, Tatzberg 41, 01307 Dresden, Germany"},{"name":"Cluster of Excellence Physics of Life, Technische Universit\u00e4t Dresden, 01307 Dresden, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Wang, P., and Heitman, J. 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