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

• Published in: Scientific reports Vol. 7; no. 1; pp. 14326 - 10
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.10.2017; Nature Publishing Group
• Subjects: 631/326/22/1294; 631/92/611; 82; 82/75; Amino acids; Angiotensin; Angiotensin II; Angiotensin II - metabolism; Angiotensin II - therapeutic use; Animals; Antimalarial agents; Antimalarials - metabolism; Antimalarials - therapeutic use; Antiprotozoal agents; Chemical Engineering; Drug Design; Drug development; Erythrocytes - drug effects; Erythrocytes - physiology; Humanities and Social Sciences; Humans; Life Cycle Stages; Life cycles; Malaria; Malaria, Falciparum - drug therapy; Malaria, Falciparum - metabolism; multidisciplinary; Peptides; Peptides - chemical synthesis; Peptides - metabolism; Peptides - therapeutic use; Plasmodium falciparum; Plasmodium falciparum - physiology; Plasmodium gallinaceum - physiology; Science; Science (multidisciplinary); Vasoconstriction; Vasoconstriction - drug effects; Vasodilator Agents - chemical synthesis; Vasodilator Agents - metabolism; Vasodilator Agents - therapeutic use
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-14642-z

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.