Tabrez Shams, Rahman Fazlur, Ali Rahat, Akand Sajjadul Kadir, Alaidarous Mohammed A, Alshehri Bader Mohammed, Banawas Saeed, Dukhyil Abdul Aziz Bin, Rub Abdur
Infection and Immunity Lab (414), Department of Biotechnology, Jamia Millia Islamia (A Central University), Delhi, New Delhi, India.
Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al Majmaah, Riyadh, Saudi Arabia.
J Cell Biochem. 2021 Apr 4. doi: 10.1002/jcb.29922.
Leishmaniasis is a neglected tropical disease caused by the protozoan parasite Leishmania. It is endemic in more than 89 different countries worldwide. Sterol alpha-14 demethylase (LdSDM), a sterol biosynthetic pathway enzyme in Leishmania donovani, plays an essential role in parasite survival and proliferation. Here, we used a drug repurposing approach to virtually screen the library of the Food and Drug Administration (FDA)-approved drugs against LdSDM to identify the potential lead-drug against leishmaniasis. Zafirlukast and avodart showed the best binding with LdSDM. Zafirlukast was tested for in vitro antileishmanial assay, but no significant effect on L. donovani promastigotes was observed even at higher concentrations. On the other hand, avodart profoundly inhibited parasite growth at relatively lower concentrations. Further, avodart showed a significant decrease in the number of intra-macrophagic amastigotes. Avodart-induced reactive oxygen species (ROS) in the parasites in a dose-dependent manner. ROS induced by avodart led to the induction of apoptosis-like cell death in the parasites as observed through annexin V/PI staining. Here, for the first time, we reported the antileishmanial activity and its possible mechanism of action of FDA-approved drug, avodart, establishing a nice example of the drug-repurposing approach. Our study suggested the possible use of avodart as an effective antileishmanial agent after further detailed validations.
利什曼病是一种由原生动物寄生虫利什曼原虫引起的被忽视的热带疾病。它在全球89个以上不同国家流行。甾醇α-14脱甲基酶（LdSDM）是杜氏利什曼原虫甾醇生物合成途径中的一种酶，在寄生虫的存活和增殖中起重要作用。在此，我们采用药物重新利用的方法，虚拟筛选美国食品药品监督管理局（FDA）批准的针对LdSDM的药物库，以确定抗利什曼病的潜在先导药物。扎鲁司特和度他雄胺与LdSDM的结合效果最佳。对扎鲁司特进行了体外抗利什曼原虫试验，但即使在高浓度下，也未观察到对杜氏利什曼原虫前鞭毛体有显著影响。另一方面，度他雄胺在相对较低的浓度下能显著抑制寄生虫生长。此外，度他雄胺使巨噬细胞内无鞭毛体数量显著减少。度他雄胺以剂量依赖的方式诱导寄生虫产生活性氧（ROS）。通过膜联蛋白V/碘化丙啶染色观察到，度他雄胺诱导的ROS导致寄生虫发生凋亡样细胞死亡。在此，我们首次报道了FDA批准的药物度他雄胺的抗利什曼原虫活性及其可能的作用机制，为药物重新利用方法树立了一个很好的典范。我们的研究表明，经过进一步详细验证后，度他雄胺有可能作为一种有效的抗利什曼原虫药物使用。
