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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
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Nature Publishing Group
2017
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| Online Access: | http://hdl.handle.net/1721.1/112690 |
| _version_ | 1826193247729352704 |
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| author | Silva, Adriana Farias Silva, Leandro Souza Alves, Flavio Lopes de Sá Pinheiro, Ana Acácia Miranda, Antonio Capurro, Margareth Lara Oliveira, Vani Xavier Der Torossian Torres, Marcelo de la Fuente Nunez, Cesar |
| author2 | MIT Synthetic Biology Center |
| author_facet | MIT Synthetic Biology Center Silva, Adriana Farias Silva, Leandro Souza Alves, Flavio Lopes de Sá Pinheiro, Ana Acácia Miranda, Antonio Capurro, Margareth Lara Oliveira, Vani Xavier Der Torossian Torres, Marcelo de la Fuente Nunez, Cesar |
| author_sort | Silva, Adriana Farias |
| collection | MIT |
| 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. |
| first_indexed | 2024-09-23T09:36:20Z |
| format | Article |
| id | mit-1721.1/112690 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T09:36:20Z |
| publishDate | 2017 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/1126902022-09-30T15:37:23Z Angiotensin II-derived constrained peptides with antiplasmodial activity and suppressed vasoconstriction Silva, Adriana Farias Silva, Leandro Souza Alves, Flavio Lopes de Sá Pinheiro, Ana Acácia Miranda, Antonio Capurro, Margareth Lara Oliveira, Vani Xavier Der Torossian Torres, Marcelo de la Fuente Nunez, Cesar MIT Synthetic Biology Center Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science Massachusetts Institute of Technology. Research Laboratory of Electronics Der Torossian Torres, Marcelo de la Fuente Nunez, Cesar 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. 2017-12-11T19:18:32Z 2017-12-11T19:18:32Z 2017-10 2017-07 2017-12-11T16:57:30Z Article http://purl.org/eprint/type/JournalArticle 2045-2322 http://hdl.handle.net/1721.1/112690 Silva, Adriana Farias et al. “Angiotensin II-Derived Constrained Peptides with Antiplasmodial Activity and Suppressed Vasoconstriction.” Scientific Reports 7, 1 (October 2017): 14326 © 2017 The Author(s) http://dx.doi.org/10.1038/s41598-017-14642-z Scientific Reports Creative Commons Attribution 4.0 International https://creativecommons.org/licenses/by/4.0/ application/pdf Nature Publishing Group Nature |
| spellingShingle | Silva, Adriana Farias Silva, Leandro Souza Alves, Flavio Lopes de Sá Pinheiro, Ana Acácia Miranda, Antonio Capurro, Margareth Lara Oliveira, Vani Xavier Der Torossian Torres, Marcelo de la Fuente Nunez, Cesar 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 |
| url | http://hdl.handle.net/1721.1/112690 |
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