Repository logo
 

A Brain-Permeable Aminosterol Regulates Cell Membranes to Mitigate the Toxicity of Diverse Pore-Forming Agents.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Kreiser, Ryan P 
Wright, Aidan K 
Sasser, Liam R 
Rinauro, Dillon J 
Gabriel, Justus M 

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.

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

Keywords

aminosterols, biotoxin neutralization, cell membranes, cellular resistance, pore-forming agents, steroid polyamines, Biological Transport, Brain, Cell Membrane

Journal Title

ACS Chem Neurosci

Conference Name

Journal ISSN

1948-7193
1948-7193

Volume Title

13

Publisher

American Chemical Society (ACS)