Nitazoxanide Inhibits the Bifunctional Enzyme GlG6PD::6PGL of Giardia lamblia: Biochemical and In Silico Characterization of a New Druggable Target.

Abstract

Giardiasis, which is caused by Giardia lamblia 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.

• Authors: Víctor Martínez-Rosas, Beatriz Hernández-Ochoa, Laura Morales-Luna, Daniel Ortega-Cuellar, Abigail González-Valdez, Roberto Arreguin-Espinosa, Yadira Rufino-González, Ernesto Calderón-Jaimes, Rosa Angélica Castillo-Rodríguez, Carlos Wong-Baeza, Isabel Baeza-Ramírez, Verónica Pérez de la Cruz, Abraham Vidal-Limón, Saúl Gómez-Manzo
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 24 Issue 14 (Jul 15 2023) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 37511272 (Publication Type: Journal Article)

Chemical References

• nitazoxanide
• Thiazoles

Topics

• Humans
• Giardia lamblia
• Giardiasis (drug therapy)
• Molecular Docking Simulation
• Thiazoles (pharmacology, therapeutic use)