{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T21:53:22Z","timestamp":1790805202583,"version":"4.1.0"},"reference-count":74,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2022,11,26]],"date-time":"2022-11-26T00:00:00Z","timestamp":1669420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Krembil Foundation","award":["GM136341"],"award-info":[{"award-number":["GM136341"]}]},{"name":"Borden Rosiak family","award":["GM136341"],"award-info":[{"award-number":["GM136341"]}]},{"name":"Arnold Irwin family","award":["GM136341"],"award-info":[{"award-number":["GM136341"]}]},{"name":"NIH R35","award":["GM136341"],"award-info":[{"award-number":["GM136341"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Several strands of investigation have established that a reduction in the levels of the cellular prion protein (PrPC) is a promising avenue for the treatment of prion diseases. We recently described an indirect approach for reducing PrPC levels that targets Na,K-ATPases (NKAs) with cardiac glycosides (CGs), causing cells to respond with the degradation of these pumps and nearby molecules, including PrPC. Because the therapeutic window of widely used CGs is narrow and their brain bioavailability is low, we set out to identify a CG with improved pharmacological properties for this indication. Starting with the CG known as oleandrin, we combined in silico modeling of CG binding poses within human NKA folds, CG structure-activity relationship (SAR) data, and predicted blood\u2013brain barrier (BBB) penetrance scores to identify CG derivatives with improved characteristics. Focusing on C4\u2032-dehydro-oleandrin as a chemically accessible shortlisted CG derivative, we show that it reaches four times higher levels in the brain than in the heart one day after subcutaneous administration, exhibits promising pharmacological properties, and suppresses steady-state PrPC levels by 84% in immortalized human cells that have been differentiated to acquire neural or astrocytic characteristics. Finally, we validate that the mechanism of action of this approach for reducing cell surface PrPC levels requires C4\u2032-dehydro-oleandrin to engage with its cognate binding pocket within the NKA \u03b1 subunit. The improved brain bioavailability of C4\u2032-dehydro-oleandrin, combined with its relatively low toxicity, make this compound an attractive lead for brain CG indications and recommends its further exploration for the treatment of prion diseases.<\/jats:p>","DOI":"10.3390\/ijms232314823","type":"journal-article","created":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T04:58:50Z","timestamp":1669784330000},"page":"14823","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Identification of a Cardiac Glycoside Exhibiting Favorable Brain Bioavailability and Potency for Reducing Levels of the Cellular Prion Protein"],"prefix":"10.3390","volume":"23","author":[{"given":"Shehab","family":"Eid","sequence":"first","affiliation":[{"name":"Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Centre, 6th Floor, 60 Leonard Avenue, Toronto, ON M5T 0S8, Canada"},{"name":"Department of Laboratory Medicine & Pathobiology, University of Toronto, Medical Sciences Building, 6th Floor, 1 King\u2019s College Circle, Toronto, ON M5S 1A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Zerbes","sequence":"additional","affiliation":[{"name":"Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Centre, 6th Floor, 60 Leonard Avenue, Toronto, ON M5T 0S8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Declan","family":"Williams","sequence":"additional","affiliation":[{"name":"Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Centre, 6th Floor, 60 Leonard Avenue, Toronto, ON M5T 0S8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinzhu","family":"Wang","sequence":"additional","affiliation":[{"name":"Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Centre, 6th Floor, 60 Leonard Avenue, Toronto, ON M5T 0S8, Canada"},{"name":"Department of Laboratory Medicine & Pathobiology, University of Toronto, Medical Sciences Building, 6th Floor, 1 King\u2019s College Circle, Toronto, ON M5S 1A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Sackmann","sequence":"additional","affiliation":[{"name":"Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Centre, 6th Floor, 60 Leonard Avenue, Toronto, ON M5T 0S8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sammy","family":"Meier","sequence":"additional","affiliation":[{"name":"Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Centre, 6th Floor, 60 Leonard Avenue, Toronto, ON M5T 0S8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nickolai O.","family":"Dulin","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Chicago, 5841 S Maryland Ave, Chicago, IL 60637, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavel","family":"Nagorny","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6962-0919","authenticated-orcid":false,"given":"Gerold","family":"Schmitt-Ulms","sequence":"additional","affiliation":[{"name":"Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Centre, 6th Floor, 60 Leonard Avenue, Toronto, ON M5T 0S8, Canada"},{"name":"Department of Laboratory Medicine & Pathobiology, University of Toronto, Medical Sciences Building, 6th Floor, 1 King\u2019s College Circle, Toronto, ON M5S 1A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"13363","DOI":"10.1073\/pnas.95.23.13363","article-title":"Prions","volume":"95","author":"Prusiner","year":"1998","journal-title":"Proc. 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