Nitazoxanide Inhibits the Bifunctional Enzyme GlG6PD::6PGL of Giardia lamblia: Biochemical and In Silico Characterization of a New Druggable Target.
Int J Mol Sci
; 24(14)2023 Jul 15.
Article
en En
| MEDLINE
| ID: mdl-37511272
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-phosphate6-phosphogluconate dehydrogenase (GlG6PD6PGL) fused enzyme as a nitazoxanide target, as NTZ behaves as a GlG6PD6PGL catalytic inhibitor. Furthermore, fluorescence assays suggest alterations in the stability of GlG6PD6PGL 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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Giardiasis
/
Giardia lamblia
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Int J Mol Sci
Año:
2023
Tipo del documento:
Article
País de afiliación:
México
Pais de publicación:
CH
/
SUIZA
/
SUÍÇA
/
SWITZERLAND