Antimicrobial peptide AR-23 derivatives with high endosomal disrupting ability enhance poly(l-lysine)-mediated gene transfer.
J Gene Med
; 22(11): e3259, 2020 11.
Article
em En
| MEDLINE
| ID: mdl-32776410
ABSTRACT
BACKGROUND:
pH-sensitive peptides are a relatively new strategy for conquering the poor endosomal release of cationic polymer-mediated transfection. Modification of antimicrobial peptides by exchanging positively-charged residues with negatively-charged glutamic acid residues (Glu) greatly improves its lytic activity at the endosomal pH, which could improve cationic polymer-mediated transfection.METHODS:
In the present study, we investigated the effect of the number of Glu substituted for positively-charged residues on the endosomal escape activity of AR-23 and the ability of mutated AR-23 with respect to enhancing cationic polymer-mediated transfection. Three analogs were synthesized by replacing the positively-charged residues in the AR-23 sequence with Glu one-by-one.RESULTS:
The pH-sensitive lysis ability of the peptides, the effect of peptides on the physicochemical characteristics, the intracellular trafficking, the transfection efficiency and the cytotoxicity of the polyplexes were determined. Increased lytic activity of peptides was observed with the increased number of Glu replacement in the AR-23 sequence at acidic pH. The number of Glu substituted for positively-charged residues of AR-23 dramatically affects its lysis ability at neutral pH. Triple-Glu substitution in the AR-23 sequence greatly improved poly(l-lysine)-mediated gene transfection efficiency at the same time as maintaining low cytotoxicity.CONCLUSIONS:
The results indicate that replacement of positively-charged residues with sufficient Glu residues may be considered as a method for designing pH-sensitive peptides, which could be applied as potential enhancers for improving cationic polymer-mediated transfection.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Polilisina
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Endossomos
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DNA
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Terapia Genética
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Proteínas Citotóxicas Formadoras de Poros
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Hemólise
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Neoplasias
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article