Abstract
Malaria is caused by the protozoa Plasmodium and is responsible for approximately one million deaths annually. The antimalarial effects of angiotensin II and its analogs against Plasmodium gallinaceum and falciparum have recently been reported. Here, 12 angiotensin II restricted analogs that contain i − (i + 2), i − (i + 3) and i − (i + 4) lactam bridges were synthesized to analyze their effect on antiplasmodial activity. To accomplish this, peptides containing two amino acid residues (aspartic or glutamic acids and lysine or ornithine), were synthesized by the t-Boc solid phase method, purified by liquid chromatography, and characterized by mass spectrometry, and conformational studies were performed by circular dichroism. The results indicate that some of the analogs had anti-plasmodium activity similar to angiotensin II (88 % activity). Among those, eight compounds exhibited high activity (>70 %), measured by fluorescence microscopy. The analogs with smaller lactam rings and an aspartic acid residue as the bridgehead element had lower levels of lytic activity. The results obtained with the new restricted analogs showed that the insertion position (near the N-terminus), the ring size, and the number of residues between the rings are as important as the components of lactam bridge, regardless of their chirality. The circular dichroism studies suggest that the active analogs, and native angiotensin II, adopt a β-fold conformation in different solutions. In conclusion, this approach provides insight for understanding the effects of restricting the ring size and position on the bioactivity of angiotensin II and provides a new direction for the design of potential chemotherapeutic agents.
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Acknowledgments
This research was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Fundação de Amparo à Pesquisa do Estado de São Paulo, (FAPESP, VXO #2011/10823-9, MDTT #2011/15083-3, AFS #2011/11448-2). 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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Marcelo D. T. Torres, Adriana F. Silva, Flavio L. Alves, Margareth L. Capurro, Antonio Miranda, and Vani X. Oliveira Jr. declare that have no conflict of interest.
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Der Torossian Torres, M., Silva, A.F., Alves, F.L. et al. The Importance of Ring Size and Position for the Antiplasmodial Activity of Angiotensin II Restricted Analogs. Int J Pept Res Ther 20, 277–287 (2014). https://doi.org/10.1007/s10989-014-9392-1
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DOI: https://doi.org/10.1007/s10989-014-9392-1