Centro de Ciências Naturais e Humanas, Universidade Federal do ABC, Santo André, SP, Brazil.
Synthetic Biology Group, MIT Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Sci Rep. 2017 Oct 30;7(1):14326. 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.
血管紧张素 II（Ang II）是一种天然的哺乳动物激素，已被描述具有抗疟原虫活性，因此构成了治疗疟疾的有前途的替代方法。尽管有希望，但由于 Ang II 强烈诱导血管收缩和在数分钟内迅速降解，因此其作为抗疟药物的开发受到限制。在这里，我们使用肽设计对 Ang II 进行靶向化学修饰，生成具有抑制血管收缩活性和增加稳定性的构象受限（二硫键交联）肽衍生物。设计的约束肽通过化学合成进行合成，然后测试其抗疟原虫活性。确定了两种先导约束肽（即肽 1 和肽 2），每个由 10 个氨基酸残基组成。这些肽在我们的鸡疟原虫（>80％）和恶性疟原虫（>40％）模型中均表现出非常有希望的活性，与 Ang II 的活性相当，并导致完全抑制血管收缩。此外，肽 5 对红细胞前期表现出选择性活性（对鸡疟原虫的活性为 98％），因此可能有可能设计针对疟疾生命周期特定阶段的肽。这里提出的 Ang II 衍生的稳定支架可能为开发新一代基于肽的疟疾治疗药物提供基础。
