A Brain-Permeable Aminosterol Regulates Cell Membranes to Mitigate the Toxicity of Diverse Pore-Forming Agents.
View / Open Files
Authors
Kreiser, Ryan P
Wright, Aidan K
Sasser, Liam R
Rinauro, Dillon J
Gabriel, Justus M
Hsu, Claire M
Hurtado, Jorge A
McKenzie, Tristan L
Albright, J Alex
Richardson, Lance
Jaffett, Victor A
Nguyen, Lam T
LeForte, Kathleen
Hollows, Jared E
Publication Date
2022-04-20Journal Title
ACS Chem Neurosci
ISSN
1948-7193
Publisher
American Chemical Society (ACS)
Volume
13
Issue
8
Pages
1219-1231
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Kreiser, R. P., Wright, A. K., Sasser, L. R., Rinauro, D. J., Gabriel, J. M., Hsu, C. M., Hurtado, J. A., et al. (2022). A Brain-Permeable Aminosterol Regulates Cell Membranes to Mitigate the Toxicity of Diverse Pore-Forming Agents.. ACS Chem Neurosci, 13 (8), 1219-1231. https://doi.org/10.1021/acschemneuro.1c00840
Description
Funder: U.S. Military Academy
Funder: Centre for Misfolding Diseases, University of Cambridge
Funder: Gates Cambridge Trust
Funder: Army Research Laboratory
Funder: Defense Threat Reduction Agency
Abstract
The molecular composition of the plasma membrane plays a key role in mediating the susceptibility of cells to perturbations induced by toxic molecules. The pharmacological regulation of the properties of the cell membrane has therefore the potential to enhance cellular resilience to a wide variety of chemical and biological compounds. In this study, we investigate the ability of claramine, a blood-brain barrier permeable small molecule in the aminosterol class, to neutralize the toxicity of acute biological threat agents, including melittin from honeybee venom and α-hemolysin from Staphylococcus aureus. Our results show that claramine neutralizes the toxicity of these pore-forming agents by preventing their interactions with cell membranes without perturbing their structures in a detectable manner. We thus demonstrate that the exogenous administration of an aminosterol can tune the properties of lipid membranes and protect cells from diverse biotoxins, including not just misfolded protein oligomers as previously shown but also biological protein-based toxins. Our results indicate that the investigation of regulators of the physicochemical properties of cell membranes offers novel opportunities to develop countermeasures against an extensive set of cytotoxic effects associated with cell membrane disruption.
Keywords
Cell membranes, Cellular Resistance, Pore-forming Agents, Aminosterols, Biotoxin Neutralization, Steroid Polyamines, Brain, Cell Membrane, Biological Transport
Identifiers
35404569, PMC9026273
External DOI: https://doi.org/10.1021/acschemneuro.1c00840
This record's URL: https://www.repository.cam.ac.uk/handle/1810/337159
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/
Statistics
Total file downloads (since January 2020). For more information on metrics see the
IRUS guide.