Laboratory of Molecular Epidemiology and Experimental Pathology - LR16IPT04, Institut Pasteur de Tunis, Université de Tunis El Manar, Tunis, Tunisia.
Front Cell Infect Microbiol. 2024 Sep 26;14:1403589. doi: 10.3389/fcimb.2024.1403589. eCollection 2024.
Drug repurposing is a promising approach towards the discovery of novel treatments against Neglected Tropical Diseases, such as Leishmaniases, presenting the advantage of reducing both costs and duration of the drug discovery process. In previous work, our group developed a Machine Learning pipeline for the repurposing of FDA-approved drugs against parasites. The present study is focused on an validation of this approach by assessing the antileishmanial effects of 10 predicted drug candidates. First, we evaluated the drugs' activity against promastigotes from two strains of and one of , which caused distinct clinical manifestations, using an MTT assay. The standard anti- drug Amphotericin B was used as a positive control. Five molecules demonstrated anti- effects, out of which Acebutolol, Prilocaine and Phenylephrine are described herein for the first time. When tested on promastigote growth, Acebutolol displayed IC values ranging from 69.28 to 145.53 µg/mL. Prilocaine exhibited IC values between 33.10 and 45.81 µg/mL. Phenylephrine, on the other hand, presented IC values >200 µg/mL. The two remaining drugs, Dibucaine and Domperidone, exhibited significantly low IC values varying between 0.58 and 1.05 µg/mL, and 6.30 and 8.17 µg/mL, respectively. Both compounds were previously described as anti- agents . All five compounds demonstrated no notable cytotoxic effects on THP-1-derived macrophages at the IC concentrations, allowing for their testing on the intracellular form of and parasites. Interestingly, all compounds exhibited antileishmanial activity on amastigotes with enhanced IC values compared to the corresponding promastigotes. Noticeably, Dibucaine and Domperidone displayed IC values of at most 1.99 µg/mL. Acebutolol, Prilocaine and Phenylephrine showed IC values ranging from 13.84 to 66.81 µg/mL. Our previously published Computer-Aided repositioning pipelines of FDA-approved drugs as antileishmanial agents identified Dibucaine and Domperidone as candidates in support of previous studies. This study consolidates such findings through the validation against 2 species, highly prevalent in Africa and Middle East, and reveals Acebutolol, Prilocaine, and Phenylephrine as novel anti- effectors, confirming the relevance of our approach and calling for further investigations.
药物重定位是一种有前途的方法，可以发现针对被忽视的热带病（如利什曼病）的新型治疗方法，具有降低药物发现过程成本和时间的优势。在之前的工作中，我们小组开发了一种用于重新定位 FDA 批准药物的机器学习管道，以对抗寄生虫。本研究通过评估 10 种预测候选药物的抗利什曼原虫作用来验证该方法。首先，我们使用 MTT 测定法评估了药物对来自两种 和一种 的前鞭毛体的活性，这两种 在临床症状上有明显的区别，使用的是阳性对照药物两性霉素 B。五种分子表现出抗 作用，其中 Acebutolol、Prilocaine 和 Phenylephrine 是首次在此文中描述。当在前鞭毛体生长上进行测试时，Acebutolol 的 IC 值范围为 69.28 至 145.53 µg/mL。Prilocaine 表现出的 IC 值在 33.10 和 45.81 µg/mL 之间。另一方面，Phenylephrine 的 IC 值>200 µg/mL。两种剩余的药物，丁卡因和多潘立酮，表现出显著低的 IC 值，分别在 0.58 和 1.05 µg/mL 之间，以及 6.30 和 8.17 µg/mL 之间。这两种化合物之前都被描述为抗 剂。在 IC 浓度下，所有五种化合物对 THP-1 衍生的巨噬细胞均没有明显的细胞毒性作用，允许在 体内形式的 和 寄生虫上进行测试。有趣的是，所有化合物在无鞭毛体上均表现出抗利什曼原虫活性，与相应的前鞭毛体相比，IC 值增强。值得注意的是，丁卡因和多潘立酮的 IC 值最高为 1.99 µg/mL。Acebutolol、Prilocaine 和 Phenylephrine 的 IC 值范围为 13.84 至 66.81 µg/mL。我们之前发表的基于计算机辅助的 FDA 批准药物再定位为抗利什曼原虫药物的管道将丁卡因和多潘立酮确定为候选药物，支持之前的研究。本研究通过对在非洲和中东高度流行的 2 个物种进行 验证，巩固了这一发现，并揭示了 Acebutolol、Prilocaine 和 Phenylephrine 作为新型抗 效应物，证实了我们方法的相关性，并呼吁进一步研究。
