Identification of a Cardiac Glycoside Exhibiting Favorable Brain Bioavailability and Potency for Reducing Levels of the Cellular Prion Protein
Abstract
:1. Introduction
2. Results
2.1. Study Design
2.2. In Silico Modeling of Oleandrin Binding to Human NKA α Subunit
2.3. Evaluation of Chemically Accessible Oleandrin Derivatives Based on Binding Score and Brain Bioavailability
2.4. Synthesis of Lead Compound with Favorable Characteristics
2.5. Analysis of Brain Bioavailability
2.6. Transepithelial Diffusion and Transport
2.7. Free Versus Bound Fraction
2.8. In Vitro Assessment of Potency in Differentiated ReN VM Cells
2.9. KDC203 Is Less Toxic Than Oleandrin
2.10. Mutagenesis of CG Binding Site within ATP1A1 Abolishes KDC203-Dependent PrPC Reduction
3. Discussion
4. Materials and Methods
4.1. Sequence Alignment and Identification of Residues Lining CG Binding Pocket
4.2. Structural Modeling and Assessment of Docking and BBB Penetrance Scores
4.3. Design of Chemically Accessible Oleandrin Derivatives
4.4. Synthesis of Shortlisted Oleandrin Derivative
4.5. Characterization of KDC203 by Mass Spectrometry
4.6. Animal Husbandry
4.7. Tritium-Based Comparison of Bioavailability of Oleandrin and KDC203
4.8. Bidirectional MDCK Assay
4.9. Rapid Equilibrium Dialysis
4.10. Treatment of ReN VM Cells with KDC203
4.11. Antibodies
4.12. Western Blot Analyses
4.13. Viability, Intracellular Ca2+, and ATP Content in Cells Exposed to KDC203 versus Oleandrin
4.14. Statistical Analyses
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
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Eid, S.; Zerbes, T.; Williams, D.; Wang, X.; Sackmann, C.; Meier, S.; Dulin, N.O.; Nagorny, P.; Schmitt-Ulms, G. Identification of a Cardiac Glycoside Exhibiting Favorable Brain Bioavailability and Potency for Reducing Levels of the Cellular Prion Protein. Int. J. Mol. Sci. 2022, 23, 14823. https://doi.org/10.3390/ijms232314823
Eid S, Zerbes T, Williams D, Wang X, Sackmann C, Meier S, Dulin NO, Nagorny P, Schmitt-Ulms G. Identification of a Cardiac Glycoside Exhibiting Favorable Brain Bioavailability and Potency for Reducing Levels of the Cellular Prion Protein. International Journal of Molecular Sciences. 2022; 23(23):14823. https://doi.org/10.3390/ijms232314823
Chicago/Turabian StyleEid, Shehab, Thomas Zerbes, Declan Williams, Xinzhu Wang, Chris Sackmann, Sammy Meier, Nickolai O. Dulin, Pavel Nagorny, and Gerold Schmitt-Ulms. 2022. "Identification of a Cardiac Glycoside Exhibiting Favorable Brain Bioavailability and Potency for Reducing Levels of the Cellular Prion Protein" International Journal of Molecular Sciences 23, no. 23: 14823. https://doi.org/10.3390/ijms232314823