Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Departamento de Patologia Clínica, COLTEC, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
J Mol Graph Model. 2019 Mar;87:89-97. doi: 10.1016/j.jmgm.2018.11.014. Epub 2018 Nov 29.
New therapeutic strategies against leishmaniasis are desirable, since the treatment against disease presents problems, such as the toxicity, high cost and/or parasite resistance. As consequence, new antileishmanial compounds are necessary to be identified, as presenting high activity against Leishmania, but low toxicity in mammalian hosts. In the present study, a Leishmania proteome mining strategy was developed, in order to select new drug targets with low homology to human proteins, but that are considered relevant for the parasite' survival. Results showed a hypothetical protein, which was functionally annotated as a glucosidase-like protein, as presenting such characteristics. This protein was associated with the metabolic network of the N-Glycan biosynthesis pathway in Leishmania, and two specific inhibitors - acarbose and miglitol - were predicted to be potential targets against it. In this context, miglitol [1-(2-Hydroxyethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol] was tested against stationary promastigotes and axenic amastigotes of the Leishmania amazonensis and L. infantum species, and results showed high values of antileishmanial inhibition against both parasite species. Miglitol showed also efficacy in the treatment of Leishmania-infected macrophages; thus denoting its potential use as an antileishmanial candidate. In conclusion, this work presents a new drug target identified by a proteome mining strategy associated with bioinformatics tools, and suggested its use as a possible candidate to be applied in the treatment against disease.
需要新的抗利什曼病治疗策略，因为该疾病的治疗存在问题，如毒性、高成本和/或寄生虫耐药性。因此，有必要确定新的抗利什曼化合物，因为它们对利什曼原虫具有高活性，但对哺乳动物宿主的毒性低。在本研究中，开发了一种利什曼蛋白质组挖掘策略，以选择与人类蛋白同源性低但被认为与寄生虫生存相关的新药物靶点。结果表明，一种假定蛋白被功能注释为糖苷酶样蛋白，具有这些特征。该蛋白与利什曼原虫 N-糖生物合成途径的代谢网络相关，并且预测两种特定抑制剂——阿卡波糖和米格列醇——可能是针对它的潜在靶点。在这种情况下，米格列醇[1-(2-羟乙基)-2-(羟甲基)哌啶-3,4,5-三醇]针对静止期前鞭毛体和无细胞内阿米巴利什曼原虫和 L. 婴儿物种进行了测试，结果表明对两种寄生虫都具有很高的抗利什曼抑制作用。米格列醇还在治疗感染利什曼原虫的巨噬细胞中显示出疗效；因此，它表示其作为抗利什曼候选药物的潜在用途。总之，这项工作通过与生物信息学工具相关的蛋白质组挖掘策略提出了一个新的药物靶点，并建议将其用作治疗疾病的候选药物。
