Haddad Houda, da Franca Rodrigues Klinger Antonio, Othman Houcemeddine, Veras Leiz Maria Costa, Rodrigues Raiza Raianne Luz, Ouahchi Ines, Ouni Bouraoui, Zaϊri Amira
BIOLIVAL Laboratory, Higher Institute of Biotechnology of Monastir ISBM, University of Monastir, 5000 Monastir, Tunisia.
Biochemistry Department, Faculty of Medicine, University of Sousse, 4002 Sousse, Tunisia.
Curr Pharm Biotechnol. 2025;26(2):276-288. doi: 10.2174/0113892010296038240427050421.
Leishmaniasis is responsible for approximately 65,000 annual deaths. Various Leishmania species are the predominant cause of visceral, cutaneous, or mucocutaneous leishmaniasis, affecting millions worldwide. The lack of a vaccine, emergence of resistance, and undesirable side effects caused by antileishmanial medications have prompted researchers to look for novel therapeutic approaches to treat this disease. Antimicrobial peptides (AMPs) offer an alternative for promoting the discovery of new drugs.
In this study, we detail the synthesis process and investigate the antileishmanial activity against for peptides belonging to the dermaseptin (DS) family and their synthetic analogs. The MTT assay was performed to investigate the cytotoxicity of these peptides on the murine macrophage cell line RAW 264.7. Subsequently, we performed molecular modeling analysis to explore the structure-function correlation of the derivatives interacting with the parasitic membrane.
All examined derivatives displayed concentration-dependent antileishmanial effect at low concentrations. Their effectiveness varied according to the peptide's proprieties. Notably, peptides with higher levels of charge demonstrated the most pronounced activities. Cytotoxicity assays showed that all the tested peptides were not cytotoxic compared to the tested conventional drug. The structure-function relationships demonstrated that the charged N-terminus could be responsible for the antileishmanial effect observed on promastigotes.
Collectively, these results propose that dermaseptins (DS) might offer potential as promising candidates for the development of effective antileishmanial therapies.
利什曼病每年导致约65000人死亡。多种利什曼原虫是内脏型、皮肤型或黏膜皮肤型利什曼病的主要病因，影响着全球数百万人。疫苗的缺乏、耐药性的出现以及抗利什曼药物引起的不良副作用促使研究人员寻找治疗这种疾病的新疗法。抗菌肽为促进新药发现提供了一种选择。
在本研究中，我们详细描述了合成过程，并研究了属于皮肤防御素（DS）家族的肽及其合成类似物对利什曼原虫的抗利什曼活性。采用MTT法研究这些肽对小鼠巨噬细胞系RAW 264.7的细胞毒性。随后，我们进行了分子模拟分析，以探索与寄生虫膜相互作用的衍生物的结构-功能关系。
所有检测的衍生物在低浓度下均表现出浓度依赖性的抗利什曼效应。它们的有效性因肽的特性而异。值得注意的是，电荷水平较高的肽表现出最显著的活性。细胞毒性试验表明，与测试的传统药物相比，所有测试的肽均无细胞毒性。结构-功能关系表明，带电荷的N端可能是前鞭毛体抗利什曼效应的原因。
总的来说，这些结果表明皮肤防御素（DS）可能有潜力成为开发有效抗利什曼疗法的有前景的候选药物。
