Abstract
Malaria is an infectious disease for which effective treatment and prevention strategies remain limited. Our group recently reported that angiotensin II (AII) presents antiplasmodial activity and inhibits the development of Plasmodium gallinaceum in Aedes aegypti. However, details concerning role of each amino acid residue in the antiplasmodial activity of the peptide and information about the minimal structure responsible for this activity remain unknown. In this work, we investigated the effects of specific deletions (i.e., mono-, di-, tri- and tetra-deletions) of AII amino acids on the antiplasmodial activity of this molecule. The peptides were synthesized on solid phase method using the t-Boc strategy, purified using high performance liquid chromatography and characterized using mass spectrometry. The lytic activity of the peptides was assessed in vitro using mature sporozoites extracted from the salivary glands of infected Aedes aegypti mosquitoes. The results demonstrate that all of the deletions reduced antiplasmodial activity compared to native AII and that active analogs tend to adopt β-turn conformations; however, the deletion of bulky hydrophobic residues causes greater reductions of bioactivity than the deletion of hydrophilic residues. Corroborating previous studies, we observed that analog extremities are susceptible to changes and can be carefully modified without compromising the activity of this compound. This research contributes to our understanding of the role of each AII amino acid residue in activity against Plasmodium gallinaceum and identifies two short analogs with similar antiplasmodial activity to AII. These analogs may be candidates for additional antimalarial assays because they are inexpensive and easy to synthesize.
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Acknowledgments
This research was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo/(FAPESP VXOJr #2008/51869-9 and 2011/10823-9, MDTT #2011/15083-3, AFS #2011/11448-2), Conselho Nacional de Desenvolvimento Científico e Tecnológico/CNPq and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/CAPES.
Conflict of interest
Luiz Henrique Rodrigues Ferreira, Adriana Farias Silva, Marcelo Der Torossian Torres, Cibele Nicolaski Pedron, Margareth Lara Capurro, Flávio Lopes Alves, Antonio Miranda and Vani Xavier Oliveira Jr. declare that have no conflict of interest.
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This study was carried out in strict accordance with the protocol approved by the Committee on the Ethics in Research of the Universidade Federal de São Paulo (Permit Number: 2013/479357) and Universidade de São Paulo (Permit number: 133). All surgery was performed under anesthesia, and all efforts were made to minimize animal suffering and all institutional and national guidelines for the care and use of laboratory animals were followed.
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Ferreira, L.H.R., Silva, A.F., Torres, M.D.T. et al. Effects of Amino Acid Deletion on the Antiplasmodial Activity of Angiotensin II. Int J Pept Res Ther 20, 553–564 (2014). https://doi.org/10.1007/s10989-014-9425-9
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DOI: https://doi.org/10.1007/s10989-014-9425-9