Tabrez Shams, Rahman Fazlur, Ali Rahat, Muhammad Fida, Alshehri Bader Mohammed, Alaidarous Mohammed A, Banawas Saeed, Dukhyil Abdul Aziz Bin, Rub Abdur
Infection and Immunity Lab (414), Department of Biotechnology, Jamia Millia Islamia (A Central University), New Delhi, India.
Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al Majmaah, Saudi Arabia.
Drug Dev Res. 2021 Dec;82(8):1154-1161. doi: 10.1002/ddr.21820. Epub 2021 Apr 30.
Leishmaniasis is a vector-borne disease caused by around 20 species of Leishmania. The main clinical forms of leishmaniasis are cutaneous leishmaniasis (CL) and visceral leishmaniasis (VL). VL is caused by Leishmania infantum in Central and South America, Mediterranean Basin, Middle East, and by L. donovani in Asia and Africa. Sterol C-24 methyltransferase (LdSMT) of L. donovani is a transferase enzyme of the sterol biosynthesis pathway. This pathway is one of the major targets for drug developments in Leishmania. Due to insufficient evidence about the exact function of SMT inside the cell and the uniqueness of the SMT enzyme in the Leishmania parasites made it a significant target for an effective drug development approach. We performed virtual screening of the Food and Drug Administration (FDA)-approved drug library against LdSMT and found simeprevir, an antiviral drug on top in the binding score. It showed a significant binding affinity with LdSMT. The binding was supported by hydrogen bonds and several other interactions. Simeprevir inhibited L. donovani growth of promastigotes with 50% inhibitory concentration (IC ) of 51.49 ± 5.87 μM. Further studies showed that simeprevir induced ROS generation in 44.7% of parasites at 125-μM concentration. Here, we for the first time reported simeprevir as an antileishmanial lead molecule using a drug repurposing approach.
利什曼病是一种由约20种利什曼原虫引起的媒介传播疾病。利什曼病的主要临床形式为皮肤利什曼病（CL）和内脏利什曼病（VL）。在中美洲、南美洲、地中海盆地、中东地区，VL由婴儿利什曼原虫引起，在亚洲和非洲则由杜氏利什曼原虫引起。杜氏利什曼原虫的甾醇C-24甲基转移酶（LdSMT）是甾醇生物合成途径中的一种转移酶。该途径是利什曼原虫药物开发的主要靶点之一。由于关于SMT在细胞内的确切功能的证据不足，且利什曼原虫寄生虫中SMT酶的独特性使其成为有效药物开发方法的重要靶点。我们对美国食品药品监督管理局（FDA）批准的药物库针对LdSMT进行了虚拟筛选，发现抗丙肝病毒药物西米普明在结合评分中位居榜首。它与LdSMT表现出显著的结合亲和力。这种结合得到了氢键和其他几种相互作用的支持。西米普明抑制前鞭毛体杜氏利什曼原虫的生长，50%抑制浓度（IC）为51.49±5.87μM。进一步研究表明，在125μM浓度下，西米普明在44.7%的寄生虫中诱导活性氧生成。在此，我们首次报道使用药物再利用方法将西米普明作为一种抗利什曼病先导分子。
