Universidade do Grande Rio (UNIGRANRIO), Rio de Janeiro, RJ, Brazil.
Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Instituto Nacional de Ciência e Tecnologia em Biologia Estrutural e Bioimagens e Centro Nacional de Biologia Estrutural e Bioimagens, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
Acta Trop. 2022 Aug;232:106484. doi: 10.1016/j.actatropica.2022.106484. Epub 2022 Apr 26.
Giardiasis is an intestinal disease caused by the parasite protozoan Giardia intestinalis. For more than five decades, the treatment of this disease has been based on compounds such as nitroimidazoles and benzimidazoles. The parasite's adverse effects and therapeutic failure are largely recognized. Therefore, it is necessary to develop new forms of chemotherapy treatment against giardiasis. Lysine deacetylases (KDACs), which remove an acetyl group from lysine residues in histone and non-histone proteins as tubulin, are found in the Giardia genome and can become an interesting option for giardiasis treatment. In the present study, we evaluated the effects of 4-[(10H-phenothiazin-10-yl)methyl]-N-hydroxybenzamide, a new class I/II KDAC inhibitor, on G. intestinalis growth, cytoskeleton, and ultrastructure organization. This compound decreased parasite proliferation and viability and displayed an IC value of 179 nM. Scanning electron microscopy revealed the presence of protrusions on the cell surface after treatment. In addition, the vacuoles containing concentric membranous lamella and glycogen granules were observed in treated trophozoites. The cell membrane appeared deformed just above these vacuoles. Alterations on the microtubular cytoskeleton of the parasite were not observed after drug exposure. The number of diving cells with incomplete cytokinesis increased after treatment, indicating that the compound can interfere in the late steps of cell division. Our results indicate that 4-[(10H-phenothiazin-10-yl)methyl]-N-hydroxybenzamide should be explored to develop new therapeutic compounds for treating giardiasis.
贾第虫病是一种由寄生虫原虫贾第虫引起的肠道疾病。五十多年来，这种疾病的治疗一直基于硝咪唑和苯并咪唑等化合物。寄生虫的不良反应和治疗失败在很大程度上是公认的。因此，有必要开发针对贾第虫病的新形式的化学治疗方法。赖氨酸去乙酰化酶（KDACs）可以从组蛋白和非组蛋白蛋白（如微管蛋白）中的赖氨酸残基上去除乙酰基，在贾第虫基因组中被发现，可能成为治疗贾第虫病的一个有趣选择。在本研究中，我们评估了 4-[(10H-吩噻嗪-10-基)甲基]-N-羟基苯甲酰胺，一种新的 I/II 类 KDAC 抑制剂，对 G. intestinalis 生长、细胞骨架和超微结构组织的影响。该化合物降低了寄生虫的增殖和活力，IC 值为 179 nM。扫描电子显微镜显示，处理后细胞表面有突起。此外，在处理的滋养体中观察到含有同心膜片和糖原颗粒的空泡。细胞膜就在这些空泡上方变形。药物暴露后，寄生虫微管细胞骨架没有发生改变。分裂不完全的潜水细胞数量增加，表明该化合物可以干扰细胞分裂的后期步骤。我们的结果表明，4-[(10H-吩噻嗪-10-基)甲基]-N-羟基苯甲酰胺应该被探索，以开发治疗贾第虫病的新治疗化合物。
