Aggregation determines the selectivity of membrane-active anticancer and antimicrobial peptides: The case of killerFLIP

Host defense peptides selectively kill bacterial and cancer cells (including those that are drug-resistant) by perturbing the permeability of their membranes, without being significantly toxic to the host. Coulombic interactions between these cationic and amphipathic peptides and the negatively char...

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Bibliographic Details
Published in:	Biochimica et biophysica acta. Biomembranes Vol. 1862; no. 2; p. 183107
Main Authors:	Vaezi, Zahra, Bortolotti, Annalisa, Luca, Vincenzo, Perilli, Giulia, Mangoni, Maria Luisa, Khosravi-Far, Roya, Bobone, Sara, Stella, Lorenzo
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier B.V 01-02-2020
Subjects:	Aggregation Antimicrobial Cationic Peptides - chemistry Antimicrobial Cationic Peptides - metabolism Antimicrobial Cationic Peptides - pharmacology Cell Membrane - drug effects Effective hydrophobicity Host defense peptides Hydrophobic and Hydrophilic Interactions Liposomes - chemistry Protein Binding Protein Multimerization Toxicity Aggregation Effective hydrophobicity Host defense peptides Toxicity
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Summary:	Host defense peptides selectively kill bacterial and cancer cells (including those that are drug-resistant) by perturbing the permeability of their membranes, without being significantly toxic to the host. Coulombic interactions between these cationic and amphipathic peptides and the negatively charged membranes of pathogenic cells contribute to the selective toxicity. However, a positive charge is not sufficient for selectivity, which can be achieved only by a finely tuned balance of electrostatic and hydrophobic driving forces. A common property of amphipathic peptides is the formation of aggregated structures in solution, but the role of this phenomenon in peptide activity and selectivity has received limited attention. Our data on the anticancer peptide killerFLIP demonstrate that aggregation strongly increases peptide selectivity, by reducing the effective peptide hydrophobicity and thus the affinity towards membranes composed of neutral lipids (like the outer layer of healthy eukaryotic cell membranes). Aggregation is therefore a useful tool to modulate the selectivity of membrane active peptides and peptidomimetics. [Display omitted] •KillerFLIP is a membrane-active anticancer peptide.•It forms aggregates above a critical concentration.•Only aggregates are selective for negatively charged versus neutral membranes.•Aggregation modulates effective hydrophobicity and thus binding selectivity.
ISSN:	0005-2736 1879-2642
DOI:	10.1016/j.bbamem.2019.183107