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

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

  • ACS Chem Neurosci. 2022 Apr 20;13(8):1219-1231. doi: 10.1021/acschemneuro.1c00840.
Ryan P Kreiser 1,  Aidan K Wright 1,  Liam R Sasser 1,  Dillon J Rinauro 2,  Justus M Gabriel 1,  Claire M Hsu 1,  Jorge A Hurtado 1,  Tristan L McKenzie 1,  Silvia Errico 2 3,  J Alex Albright 1,  Lance Richardson 1,  Victor A Jaffett 1,  Dawn E Riegner 1,  Lam T Nguyen 1,  Kathleen LeForte 1,  Michael Zasloff 4,  Jared E Hollows 1,  Fabrizio Chiti 3,  Michele Vendruscolo 2,  Ryan Limbocker 1
Affiliations

Affiliations

  • 1 Department of Chemistry and Life Science, United States Military Academy, West Point, New York 10996, United States.
  • 2 Centre for Misfolding Diseases, Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.
  • 3 Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50134, Italy.
  • 4 MedStar-Georgetown Transplant Institute, Georgetown University School of Medicine, Washington, District of Columbia 20010, United States.
PMID: 35404569 DOI: 10.1021/acschemneuro.1c00840
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

aminosterols; biotoxin neutralization; cell membranes; cellular resistance; pore-forming agents; steroid polyamines.

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