Laboratório Multidisciplinar de Pesquisa, Universidade São Francisco, Bragança Paulista, SP, Brazil.
Departamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP, Brazil.
Bioorg Chem. 2021 Apr;109:104709. doi: 10.1016/j.bioorg.2021.104709. Epub 2021 Feb 9.
The sickle cell disease (SCD) has a genetic cause, characterized by a replacement of glutamic acid to valine in the β-chain of hemoglobin. The disease has no effective treatment so far, and patients suffer a range from acute to chronic complications that include chronic hemolytic anemia, vaso-occlusive ischemia, pain, acute thoracic syndrome, cerebrovascular accident, nephropathy, osteonecrosis and reduced lifetime. The oxidation in certain regions of the hemoglobin favors the reactive oxygen species (ROS) formation, which is the cause of many clinical manifestations. Antioxidants have been studied to reduce the hemoglobin ROS levels, and in this sense, we have searched for new antioxidants glucal-based triazoles compounds with anti-sickling activity. Thirty analogues were synthetized and tested in in vitro antioxidant assays. Two of them were selected based in their effects and concentration-response activity and conducted to in cell assays. Both molecules did not cause any hemolysis and could reduce the red blood cell damage caused by hydrogen peroxide, in a model of oxidative stress induction that mimics the SCD. Moreover, one molecule (termed 11m), besides reducing the hemolysis, was able to prevent the cell damage caused by the hydrogen peroxide. Later on, by in silico pharmacokinetics analysis, we could see that 11m has appropriated proprieties for druggability and the probable mechanism of action is the binding to Peroxiredoxin-5, an antioxidant enzyme that reduces the hydrogen peroxide levels, verified after molecular docking assays. Thus, starting from 30 glucal-based triazoles molecules in a structure-activity relationship, we could select one with antioxidant proprieties that could act on RBC to reduce the oxidative stress, being useful for the treatment of SCD.
镰状细胞病（SCD）具有遗传原因，其特征在于血红蛋白β链中谷氨酸被缬氨酸取代。迄今为止，该病尚无有效治疗方法，患者会遭受一系列从急性到慢性的并发症，包括慢性溶血性贫血、血管阻塞性缺血、疼痛、急性胸综合征、脑血管意外、肾病、骨坏死和寿命缩短。血红蛋白某些区域的氧化作用有利于活性氧（ROS）的形成，这是许多临床表现的原因。抗氧化剂已被研究用于降低血红蛋白 ROS 水平，在这种意义上，我们已经寻找具有抗镰变活性的基于葡糖醛酸的三唑类化合物的新型抗氧化剂。合成了 30 种类似物，并在体外抗氧化测定中进行了测试。根据它们的效果和浓度反应活性选择了两种，并进行了细胞测定。这两种分子都不会引起溶血，并且可以减少由过氧化氢引起的红细胞损伤，在一种模拟 SCD 的氧化应激诱导模型中。此外，一种分子（称为 11m），除了减少溶血外，还能够预防由过氧化氢引起的细胞损伤。后来，通过计算机药代动力学分析，我们可以看到 11m 具有适当的成药性，其可能的作用机制是与抗氧化酶 Peroxiredoxin-5 结合，该酶可降低过氧化氢水平，在分子对接测定后得到验证。因此，从 30 种基于葡糖醛酸的三唑类分子的结构-活性关系出发，我们可以选择一种具有抗氧化特性的分子，该分子可以作用于 RBC 以减轻氧化应激，从而有助于治疗 SCD。
