Laboratorio de Bioquímica Genética, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City 04530, Mexico.
Programa de Posgrado en Biomedicina y Biotecnología Molecular, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City 11340, Mexico.
Int J Mol Sci. 2023 Jul 15;24(14):11516. doi: 10.3390/ijms241411516.
Giardiasis, which is caused by infection, is a relevant cause of morbidity and mortality worldwide. Because no vaccines are currently available to treat giardiasis, chemotherapeutic drugs are the main options for controlling infection. Evidence has shown that the nitro drug nitazoxanide (NTZ) is a commonly prescribed treatment for giardiasis; however, the mechanisms underlying NTZ's antigiardial activity are not well-understood. Herein, we identified the glucose-6-phosphate::6-phosphogluconate dehydrogenase (GlG6PD::6PGL) fused enzyme as a nitazoxanide target, as NTZ behaves as a GlG6PD::6PGL catalytic inhibitor. Furthermore, fluorescence assays suggest alterations in the stability of GlG6PD::6PGL protein, whereas the results indicate a loss of catalytic activity due to conformational and folding changes. Molecular docking and dynamic simulation studies suggest a model of NTZ binding on the active site of the G6PD domain and near the structural NADP binding site. The findings of this study provide a novel mechanistic basis and strategy for the antigiardial activity of the NTZ drug.
贾第虫病是由 感染引起的，是全球发病率和死亡率的相关原因。由于目前尚无治疗贾第虫病的疫苗，化学治疗药物是控制感染的主要选择。有证据表明，硝基药物硝唑尼特（NTZ）是一种常用的贾第虫病治疗方法；然而，硝唑尼特的抗贾第虫活性的机制尚不清楚。在此，我们将葡萄糖-6-磷酸：6-磷酸葡萄糖脱氢酶（GlG6PD：6PGL）融合酶鉴定为硝唑尼特的靶标，因为硝唑尼特是 GlG6PD：6PGL 的催化抑制剂。此外，荧光分析表明 GlG6PD：6PGL 蛋白稳定性发生改变，而结果表明由于构象和折叠变化导致催化活性丧失。分子对接和动态模拟研究表明了 NTZ 结合在 G6PD 结构域的活性位点和 NADP 结合位点附近的模型。这项研究的结果为 NTZ 药物的抗贾第虫活性提供了新的机制基础和策略。
