Abstract：
OBJECTIVE: Leishmaniasis, caused by the protozoan parasite poses a significant health burden globally. With a very few specific drugs, increased drug resistance it is important to look for drug repurposing along with the identification of pre-clinical candidates against visceral leishmaniasis. This study aims to identify potential drug candidates against visceral leishmaniasis by targeting leishmanial MAP kinases and screening FDA approved protein kinase inhibitors.
METHODS: MAP kinases were identified from the Leishmania genome. 12 FDA approved protein kinase inhibitors were screened against Leishmania MAP kinases. Binding affinity, ADME and toxicity of identified drug candidates were profiled. The anti-proliferative effects and mechanism of action were assessed in Leishmania, including changes in cell morphology, flagellar length, cell cycle progression, reactive oxygen species (ROS) generation, and intra-macrophage parasitic burden.
RESULTS: 23 MAP kinases were identified from the Leishmania genome. Sorafenib and imatinib emerged as repurposable drug candidates and demonstrated excellent anti-proliferative effects in Leishmania. Treatment with these inhibitors resulted in significant changes in cell morphology, flagellar length, and cell cycle arrest. Furthermore, sorafenib and imatinib promoted ROS generation and reduced intra-macrophage parasitic burden, and elicited anti-leishmanial activity in in vivo experimental VL models.
CONCLUSIONS: Collectively, these results imply involvement of MAP kinases in infectivity and survival of the parasite and can pave the avenue for repurposing sorafenib and imatinib as anti-leishmanial agents. These findings contribute to the exploration of new treatment options for visceral leishmaniasis, particularly in the context of emerging drug resistance.
METHODS: MAP kinases were identified from the Leishmania genome. 12 FDA approved protein kinase inhibitors were screened against Leishmania MAP kinases. Binding affinity, ADME and toxicity of identified drug candidates were profiled. The anti-proliferative effects and mechanism of action were assessed in Leishmania, including changes in cell morphology, flagellar length, cell cycle progression, reactive oxygen species (ROS) generation, and intra-macrophage parasitic burden.
RESULTS: 23 MAP kinases were identified from the Leishmania genome. Sorafenib and imatinib emerged as repurposable drug candidates and demonstrated excellent anti-proliferative effects in Leishmania. Treatment with these inhibitors resulted in significant changes in cell morphology, flagellar length, and cell cycle arrest. Furthermore, sorafenib and imatinib promoted ROS generation and reduced intra-macrophage parasitic burden, and elicited anti-leishmanial activity in in vivo experimental VL models.
CONCLUSIONS: Collectively, these results imply involvement of MAP kinases in infectivity and survival of the parasite and can pave the avenue for repurposing sorafenib and imatinib as anti-leishmanial agents. These findings contribute to the exploration of new treatment options for visceral leishmaniasis, particularly in the context of emerging drug resistance.
摘要：
目标：利什曼病，由原生动物寄生虫引起的，在全球范围内构成了巨大的健康负担。只有极少数特定的药物，耐药性增加，重要的是寻找药物的再利用以及识别针对内脏利什曼病的临床前候选药物。本研究旨在通过靶向利什曼菌MAP激酶和筛选FDA批准的蛋白激酶抑制剂来确定针对内脏利什曼病的潜在候选药物。
方法：从利什曼原虫基因组中鉴定出MAP激酶。针对利什曼原虫MAP激酶筛选了12种FDA批准的蛋白激酶抑制剂。结合亲和力，对确定的候选药物的ADME和毒性进行了分析。在利什曼原虫中评估了抗增殖作用和作用机制，包括细胞形态的变化，鞭毛长度,细胞周期进程，活性氧（ROS）的产生，和巨噬细胞内寄生负担。
结果：从利什曼原虫基因组中鉴定出23种MAP激酶。索拉非尼和伊马替尼作为可再利用的候选药物出现，并在利什曼原虫中表现出优异的抗增殖作用。用这些抑制剂治疗导致细胞形态的显著变化，鞭毛长度,和细胞周期停滞。此外，索拉非尼和伊马替尼促进了ROS的产生并减少了巨噬细胞内的寄生负荷，并在体内实验VL模型中引发抗利什曼虫活性。
结论：总的来说，这些结果暗示MAP激酶参与了该寄生虫的感染性和存活,并可为索拉非尼和伊马替尼作为抗利什曼原药的再利用铺平道路.这些发现有助于探索内脏利什曼病的新治疗方案，特别是在出现耐药性的背景下。
方法：从利什曼原虫基因组中鉴定出MAP激酶。针对利什曼原虫MAP激酶筛选了12种FDA批准的蛋白激酶抑制剂。结合亲和力，对确定的候选药物的ADME和毒性进行了分析。在利什曼原虫中评估了抗增殖作用和作用机制，包括细胞形态的变化，鞭毛长度,细胞周期进程，活性氧（ROS）的产生，和巨噬细胞内寄生负担。
结果：从利什曼原虫基因组中鉴定出23种MAP激酶。索拉非尼和伊马替尼作为可再利用的候选药物出现，并在利什曼原虫中表现出优异的抗增殖作用。用这些抑制剂治疗导致细胞形态的显著变化，鞭毛长度,和细胞周期停滞。此外，索拉非尼和伊马替尼促进了ROS的产生并减少了巨噬细胞内的寄生负荷，并在体内实验VL模型中引发抗利什曼虫活性。
结论：总的来说，这些结果暗示MAP激酶参与了该寄生虫的感染性和存活,并可为索拉非尼和伊马替尼作为抗利什曼原药的再利用铺平道路.这些发现有助于探索内脏利什曼病的新治疗方案，特别是在出现耐药性的背景下。
