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Improved Cell Selectivity of Pseudin-2 via Substitution in the Leucine-Zipper Motif: In Vitro and In Vivo Antifungal Activity

Several antimicrobial peptides (AMPs) have been discovered, developed, and purified from natural sources and peptide engineering; however, the clinical applications of these AMPs are limited owing to their lack of abundance and side effects related to cytotoxicity, immunogenicity, and hemolytic acti...

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Autores principales: Park, Seong-Cheol, Kim, Heabin, Kim, Jin-Young, Kim, Hyeonseok, Cheong, Gang-Won, Lee, Jung Ro, Jang, Mi-Kyeong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766124/
https://www.ncbi.nlm.nih.gov/pubmed/33352972
http://dx.doi.org/10.3390/antibiotics9120921
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author Park, Seong-Cheol
Kim, Heabin
Kim, Jin-Young
Kim, Hyeonseok
Cheong, Gang-Won
Lee, Jung Ro
Jang, Mi-Kyeong
author_facet Park, Seong-Cheol
Kim, Heabin
Kim, Jin-Young
Kim, Hyeonseok
Cheong, Gang-Won
Lee, Jung Ro
Jang, Mi-Kyeong
author_sort Park, Seong-Cheol
collection PubMed
description Several antimicrobial peptides (AMPs) have been discovered, developed, and purified from natural sources and peptide engineering; however, the clinical applications of these AMPs are limited owing to their lack of abundance and side effects related to cytotoxicity, immunogenicity, and hemolytic activity. Accordingly, to improve cell selectivity for pseudin-2, an AMP from Pseudis paradoxa skin, in mammalian cells and pathogenic fungi, the sequence of pseudin-2 was modified by alanine or lysine at each position of two amino acids within the leucine-zipper motif. Alanine-substituted variants were highly selective toward fungi over HaCaT and erythrocytes and maintained their antifungal activities and mode of action (membranolysis). However, the antifungal activities of lysine-substituted peptides were reduced, and the compound could penetrate into fungal cells, followed by induction of mitochondrial reactive oxygen species and cell death. In vivo antifungal assays of analogous peptide showed excellent antifungal efficiency in a Candida tropicalis skin infection mouse model. Our results demonstrated the usefulness of selective amino acid substitution in the repeated sequence of the leucine-zipper motif for the design of AMPs with potent antimicrobial activities and low toxicity.
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spelling pubmed-77661242020-12-28 Improved Cell Selectivity of Pseudin-2 via Substitution in the Leucine-Zipper Motif: In Vitro and In Vivo Antifungal Activity Park, Seong-Cheol Kim, Heabin Kim, Jin-Young Kim, Hyeonseok Cheong, Gang-Won Lee, Jung Ro Jang, Mi-Kyeong Antibiotics (Basel) Article Several antimicrobial peptides (AMPs) have been discovered, developed, and purified from natural sources and peptide engineering; however, the clinical applications of these AMPs are limited owing to their lack of abundance and side effects related to cytotoxicity, immunogenicity, and hemolytic activity. Accordingly, to improve cell selectivity for pseudin-2, an AMP from Pseudis paradoxa skin, in mammalian cells and pathogenic fungi, the sequence of pseudin-2 was modified by alanine or lysine at each position of two amino acids within the leucine-zipper motif. Alanine-substituted variants were highly selective toward fungi over HaCaT and erythrocytes and maintained their antifungal activities and mode of action (membranolysis). However, the antifungal activities of lysine-substituted peptides were reduced, and the compound could penetrate into fungal cells, followed by induction of mitochondrial reactive oxygen species and cell death. In vivo antifungal assays of analogous peptide showed excellent antifungal efficiency in a Candida tropicalis skin infection mouse model. Our results demonstrated the usefulness of selective amino acid substitution in the repeated sequence of the leucine-zipper motif for the design of AMPs with potent antimicrobial activities and low toxicity. MDPI 2020-12-18 /pmc/articles/PMC7766124/ /pubmed/33352972 http://dx.doi.org/10.3390/antibiotics9120921 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Park, Seong-Cheol
Kim, Heabin
Kim, Jin-Young
Kim, Hyeonseok
Cheong, Gang-Won
Lee, Jung Ro
Jang, Mi-Kyeong
Improved Cell Selectivity of Pseudin-2 via Substitution in the Leucine-Zipper Motif: In Vitro and In Vivo Antifungal Activity
title Improved Cell Selectivity of Pseudin-2 via Substitution in the Leucine-Zipper Motif: In Vitro and In Vivo Antifungal Activity
title_full Improved Cell Selectivity of Pseudin-2 via Substitution in the Leucine-Zipper Motif: In Vitro and In Vivo Antifungal Activity
title_fullStr Improved Cell Selectivity of Pseudin-2 via Substitution in the Leucine-Zipper Motif: In Vitro and In Vivo Antifungal Activity
title_full_unstemmed Improved Cell Selectivity of Pseudin-2 via Substitution in the Leucine-Zipper Motif: In Vitro and In Vivo Antifungal Activity
title_short Improved Cell Selectivity of Pseudin-2 via Substitution in the Leucine-Zipper Motif: In Vitro and In Vivo Antifungal Activity
title_sort improved cell selectivity of pseudin-2 via substitution in the leucine-zipper motif: in vitro and in vivo antifungal activity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766124/
https://www.ncbi.nlm.nih.gov/pubmed/33352972
http://dx.doi.org/10.3390/antibiotics9120921
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