Natural proteinaceous pore-forming agents can bind and permeabilize cell membranes, leading to ion dyshomeostasis and cell death. In the search for antidotes that can protect cells from peptide toxins, we discovered that the polyphenol epigallocatechin gallate (EGCG) interacts directly with melittin from honeybee venom, resulting in the elimination of its binding to the cell membrane and toxicity by markedly lowering the extent of its solvent-exposed hydrophobicity and promoting its oligomerization into larger species. These physicochemical parameters have also been shown to play a key role in the binding to cells of misfolded protein oligomers in a host of neurodegenerative diseases, where oligomer-membrane binding and associated toxicity have been shown to correlate negatively with oligomer size and positively with solvent-exposed hydrophobicity. For melittin, which is not an amyloid-forming protein and has a very distinct mechanism of toxicity compared to misfolded oligomers, we find that the size-hydrophobicity-toxicity relationship also rationalizes the pharmacological attenuation of melittin toxicity by EGCG. These results highlight the importance of the physicochemical properties of pore forming agents in mediating their interactions with cell membranes and suggest a possible therapeutic approach based on compounds with a similar mechanism of action as EGCG.

EGCG inactivates a pore-forming toxin by promoting its oligomerization and decreasing its solvent-exposed hydrophobicity / Justus M Gabriel, Thomas Tan, Dillon J Rinauro, Claire M Hsu, Caleb J Buettner, Marshall Gilmer, Amrita Kaur, Tristan L McKenzie, Martin Park, Sophie Cohen, Silvia Errico, Aidan K Wright, Fabrizio Chiti, Michele Vendruscolo, Ryan Limbocker. - In: CHEMICO-BIOLOGICAL INTERACTIONS. - ISSN 0009-2797. - ELETTRONICO. - 371:(2023), pp. 110307-110307. [10.1016/j.cbi.2022.110307]

EGCG inactivates a pore-forming toxin by promoting its oligomerization and decreasing its solvent-exposed hydrophobicity

Silvia Errico;Fabrizio Chiti;
2023

Abstract

Natural proteinaceous pore-forming agents can bind and permeabilize cell membranes, leading to ion dyshomeostasis and cell death. In the search for antidotes that can protect cells from peptide toxins, we discovered that the polyphenol epigallocatechin gallate (EGCG) interacts directly with melittin from honeybee venom, resulting in the elimination of its binding to the cell membrane and toxicity by markedly lowering the extent of its solvent-exposed hydrophobicity and promoting its oligomerization into larger species. These physicochemical parameters have also been shown to play a key role in the binding to cells of misfolded protein oligomers in a host of neurodegenerative diseases, where oligomer-membrane binding and associated toxicity have been shown to correlate negatively with oligomer size and positively with solvent-exposed hydrophobicity. For melittin, which is not an amyloid-forming protein and has a very distinct mechanism of toxicity compared to misfolded oligomers, we find that the size-hydrophobicity-toxicity relationship also rationalizes the pharmacological attenuation of melittin toxicity by EGCG. These results highlight the importance of the physicochemical properties of pore forming agents in mediating their interactions with cell membranes and suggest a possible therapeutic approach based on compounds with a similar mechanism of action as EGCG.
2023
371
110307
110307
Justus M Gabriel, Thomas Tan, Dillon J Rinauro, Claire M Hsu, Caleb J Buettner, Marshall Gilmer, Amrita Kaur, Tristan L McKenzie, Martin Park, Sophie Cohen, Silvia Errico, Aidan K Wright, Fabrizio Chiti, Michele Vendruscolo, Ryan Limbocker
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1311900
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