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Angiotensin II-derived constrained peptides with antiplasmodial activity and suppressed vasoconstriction

Angiotensin II (Ang II) is a natural mammalian hormone that has been described to exhibit antiplasmodial activity therefore constituting a promising alternative for the treatment of malaria. Despite its promise, the development of Ang II as an antimalarial is limited by its potent induction of vasoc...

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Autores principales: Silva, Adriana Farias, Torres, Marcelo Der Torossian, Silva, Leandro Souza, Alves, Flavio Lopes, de Sá Pinheiro, Ana Acácia, Miranda, Antonio, Capurro, Margareth Lara, de la Fuente-Nunez, Cesar, Oliveira, Vani Xavier
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662717/
https://www.ncbi.nlm.nih.gov/pubmed/29085013
http://dx.doi.org/10.1038/s41598-017-14642-z
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author Silva, Adriana Farias
Torres, Marcelo Der Torossian
Silva, Leandro Souza
Alves, Flavio Lopes
de Sá Pinheiro, Ana Acácia
Miranda, Antonio
Capurro, Margareth Lara
de la Fuente-Nunez, Cesar
Oliveira, Vani Xavier
author_facet Silva, Adriana Farias
Torres, Marcelo Der Torossian
Silva, Leandro Souza
Alves, Flavio Lopes
de Sá Pinheiro, Ana Acácia
Miranda, Antonio
Capurro, Margareth Lara
de la Fuente-Nunez, Cesar
Oliveira, Vani Xavier
author_sort Silva, Adriana Farias
collection PubMed
description Angiotensin II (Ang II) is a natural mammalian hormone that has been described to exhibit antiplasmodial activity therefore constituting a promising alternative for the treatment of malaria. Despite its promise, the development of Ang II as an antimalarial is limited by its potent induction of vasoconstriction and its rapid degradation within minutes. Here, we used peptide design to perform targeted chemical modifications to Ang II to generate conformationally restricted (disulfide-crosslinked) peptide derivatives with suppressed vasoconstrictor activity and increased stability. Designed constrained peptides were synthesized chemically and then tested for antiplasmodial activity. Two lead constrained peptides were identified (i.e., peptides 1 and 2), each composed of 10 amino acid residues. These peptides exhibited very promising activity in both our Plasmodium gallinaceum (>80%) and Plasmodium falciparum (>40%) models, an activity that was equivalent to that of Ang II, and led to complete suppression of vasoconstriction. In addition, peptide 5 exhibited selective activity towards the pre-erythrocytic stage (98% of activity against P. gallinaceum), thus suggesting that it may be possible to design peptides that target specific stages of the malaria life cycle. The Ang II derived stable scaffolds presented here may provide the basis for development of a new generation of peptide-based drugs for the treatment of malaria.
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spelling pubmed-56627172017-11-08 Angiotensin II-derived constrained peptides with antiplasmodial activity and suppressed vasoconstriction Silva, Adriana Farias Torres, Marcelo Der Torossian Silva, Leandro Souza Alves, Flavio Lopes de Sá Pinheiro, Ana Acácia Miranda, Antonio Capurro, Margareth Lara de la Fuente-Nunez, Cesar Oliveira, Vani Xavier Sci Rep Article Angiotensin II (Ang II) is a natural mammalian hormone that has been described to exhibit antiplasmodial activity therefore constituting a promising alternative for the treatment of malaria. Despite its promise, the development of Ang II as an antimalarial is limited by its potent induction of vasoconstriction and its rapid degradation within minutes. Here, we used peptide design to perform targeted chemical modifications to Ang II to generate conformationally restricted (disulfide-crosslinked) peptide derivatives with suppressed vasoconstrictor activity and increased stability. Designed constrained peptides were synthesized chemically and then tested for antiplasmodial activity. Two lead constrained peptides were identified (i.e., peptides 1 and 2), each composed of 10 amino acid residues. These peptides exhibited very promising activity in both our Plasmodium gallinaceum (>80%) and Plasmodium falciparum (>40%) models, an activity that was equivalent to that of Ang II, and led to complete suppression of vasoconstriction. In addition, peptide 5 exhibited selective activity towards the pre-erythrocytic stage (98% of activity against P. gallinaceum), thus suggesting that it may be possible to design peptides that target specific stages of the malaria life cycle. The Ang II derived stable scaffolds presented here may provide the basis for development of a new generation of peptide-based drugs for the treatment of malaria. Nature Publishing Group UK 2017-10-30 /pmc/articles/PMC5662717/ /pubmed/29085013 http://dx.doi.org/10.1038/s41598-017-14642-z Text en © The Author(s) 2017 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
Silva, Adriana Farias
Torres, Marcelo Der Torossian
Silva, Leandro Souza
Alves, Flavio Lopes
de Sá Pinheiro, Ana Acácia
Miranda, Antonio
Capurro, Margareth Lara
de la Fuente-Nunez, Cesar
Oliveira, Vani Xavier
Angiotensin II-derived constrained peptides with antiplasmodial activity and suppressed vasoconstriction
title Angiotensin II-derived constrained peptides with antiplasmodial activity and suppressed vasoconstriction
title_full Angiotensin II-derived constrained peptides with antiplasmodial activity and suppressed vasoconstriction
title_fullStr Angiotensin II-derived constrained peptides with antiplasmodial activity and suppressed vasoconstriction
title_full_unstemmed Angiotensin II-derived constrained peptides with antiplasmodial activity and suppressed vasoconstriction
title_short Angiotensin II-derived constrained peptides with antiplasmodial activity and suppressed vasoconstriction
title_sort angiotensin ii-derived constrained peptides with antiplasmodial activity and suppressed vasoconstriction
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662717/
https://www.ncbi.nlm.nih.gov/pubmed/29085013
http://dx.doi.org/10.1038/s41598-017-14642-z
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