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Correlation between hemolytic activity, cytotoxicity and systemic in vivo toxicity of synthetic antimicrobial peptides

The use of non-standard toxicity models is a hurdle in the early development of antimicrobial peptides towards clinical applications. Herein we report an extensive in vitro and in vivo toxicity study of a library of 24 peptide-based antimicrobials with narrow spectrum activity towards veterinary pat...

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Autores principales: Greco, Ines, Molchanova, Natalia, Holmedal, Elin, Jenssen, Håvard, Hummel, Bernard D., Watts, Jeffrey L., Håkansson, Joakim, Hansen, Paul R., Svenson, Johan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414031/
https://www.ncbi.nlm.nih.gov/pubmed/32764602
http://dx.doi.org/10.1038/s41598-020-69995-9
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author Greco, Ines
Molchanova, Natalia
Holmedal, Elin
Jenssen, Håvard
Hummel, Bernard D.
Watts, Jeffrey L.
Håkansson, Joakim
Hansen, Paul R.
Svenson, Johan
author_facet Greco, Ines
Molchanova, Natalia
Holmedal, Elin
Jenssen, Håvard
Hummel, Bernard D.
Watts, Jeffrey L.
Håkansson, Joakim
Hansen, Paul R.
Svenson, Johan
author_sort Greco, Ines
collection PubMed
description The use of non-standard toxicity models is a hurdle in the early development of antimicrobial peptides towards clinical applications. Herein we report an extensive in vitro and in vivo toxicity study of a library of 24 peptide-based antimicrobials with narrow spectrum activity towards veterinary pathogens. The haemolytic activity of the compounds was evaluated against four different species and the relative sensitivity against the compounds was highest for canine erythrocytes, intermediate for rat and human cells and lowest for bovine cells. Selected peptides were additionally evaluated against HeLa, HaCaT and HepG2 cells which showed increased stability towards the peptides. Therapeutic indexes of 50–500 suggest significant cellular selectivity in comparison to bacterial cells. Three peptides were administered to rats in intravenous acute dose toxicity studies up to 2–8 × MIC. None of the injected compounds induced any systemic toxic effects in vivo at the concentrations employed illustrating that the correlation between the different assays is not obvious. This work sheds light on the in vitro and in vivo toxicity of this class of promising compounds and provides insights into the relationship between the different toxicity models often employed in different manners to evaluate the toxicity of novel bioactive compounds in general.
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spelling pubmed-74140312020-08-10 Correlation between hemolytic activity, cytotoxicity and systemic in vivo toxicity of synthetic antimicrobial peptides Greco, Ines Molchanova, Natalia Holmedal, Elin Jenssen, Håvard Hummel, Bernard D. Watts, Jeffrey L. Håkansson, Joakim Hansen, Paul R. Svenson, Johan Sci Rep Article The use of non-standard toxicity models is a hurdle in the early development of antimicrobial peptides towards clinical applications. Herein we report an extensive in vitro and in vivo toxicity study of a library of 24 peptide-based antimicrobials with narrow spectrum activity towards veterinary pathogens. The haemolytic activity of the compounds was evaluated against four different species and the relative sensitivity against the compounds was highest for canine erythrocytes, intermediate for rat and human cells and lowest for bovine cells. Selected peptides were additionally evaluated against HeLa, HaCaT and HepG2 cells which showed increased stability towards the peptides. Therapeutic indexes of 50–500 suggest significant cellular selectivity in comparison to bacterial cells. Three peptides were administered to rats in intravenous acute dose toxicity studies up to 2–8 × MIC. None of the injected compounds induced any systemic toxic effects in vivo at the concentrations employed illustrating that the correlation between the different assays is not obvious. This work sheds light on the in vitro and in vivo toxicity of this class of promising compounds and provides insights into the relationship between the different toxicity models often employed in different manners to evaluate the toxicity of novel bioactive compounds in general. Nature Publishing Group UK 2020-08-06 /pmc/articles/PMC7414031/ /pubmed/32764602 http://dx.doi.org/10.1038/s41598-020-69995-9 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Greco, Ines
Molchanova, Natalia
Holmedal, Elin
Jenssen, Håvard
Hummel, Bernard D.
Watts, Jeffrey L.
Håkansson, Joakim
Hansen, Paul R.
Svenson, Johan
Correlation between hemolytic activity, cytotoxicity and systemic in vivo toxicity of synthetic antimicrobial peptides
title Correlation between hemolytic activity, cytotoxicity and systemic in vivo toxicity of synthetic antimicrobial peptides
title_full Correlation between hemolytic activity, cytotoxicity and systemic in vivo toxicity of synthetic antimicrobial peptides
title_fullStr Correlation between hemolytic activity, cytotoxicity and systemic in vivo toxicity of synthetic antimicrobial peptides
title_full_unstemmed Correlation between hemolytic activity, cytotoxicity and systemic in vivo toxicity of synthetic antimicrobial peptides
title_short Correlation between hemolytic activity, cytotoxicity and systemic in vivo toxicity of synthetic antimicrobial peptides
title_sort correlation between hemolytic activity, cytotoxicity and systemic in vivo toxicity of synthetic antimicrobial peptides
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414031/
https://www.ncbi.nlm.nih.gov/pubmed/32764602
http://dx.doi.org/10.1038/s41598-020-69995-9
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