Identification of a Cardiac Glycoside Exhibiting Favorable Brain Bioavailability and Potency for Reducing Levels of the Cellular Prion Protein

Several strands of investigation have established that a reduction in the levels of the cellular prion protein (PrP ) is a promising avenue for the treatment of prion diseases. We recently described an indirect approach for reducing PrP levels that targets Na,K-ATPases (NKAs) with cardiac glycosides...

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Bibliographic Details
Published in:	International journal of molecular sciences Vol. 23; no. 23; p. 14823
Main Authors:	Eid, Shehab, Zerbes, Thomas, Williams, Declan, Wang, Xinzhu, Sackmann, Chris, Meier, Sammy, Dulin, Nickolai O, Nagorny, Pavel, Schmitt-Ulms, Gerold
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 26-11-2022 MDPI
Subjects:	Alzheimer's disease Amino acids Binding Bioavailability Blood-brain barrier Brain Brain - metabolism C4′-dehydro-oleandrin Cardiac glycosides Cardiac Glycosides - therapeutic use Cell differentiation Cell surface Creutzfeldt-Jakob disease Creutzfeldt-Jakob Syndrome - metabolism Glycosides Humans Ligands Na,K-ATPases Pharmacology Prion Diseases - drug therapy Prion Diseases - metabolism Prion protein Prion Proteins - metabolism Prions - metabolism Proteins Toxicity Na,K-ATPases cardiac glycosides C4′-dehydro-oleandrin Creutzfeldt-Jakob disease prion protein
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Summary:	Several strands of investigation have established that a reduction in the levels of the cellular prion protein (PrP ) is a promising avenue for the treatment of prion diseases. We recently described an indirect approach for reducing PrP 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 PrP . 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-brain barrier (BBB) penetrance scores to identify CG derivatives with improved characteristics. Focusing on C4'-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 PrP 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 PrP levels requires C4'-dehydro-oleandrin to engage with its cognate binding pocket within the NKA α subunit. The improved brain bioavailability of C4'-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.
ISSN:	1422-0067 1661-6596 1422-0067
DOI:	10.3390/ijms232314823