Nitazoxanide Inhibits the Bifunctional Enzyme GlG6PD::6PGL of Giardia lamblia: Biochemical and In Silico Characterization of a New Druggable Target
Por:
Martinez-Rosas, Victor, Hernandez-Ochoa, Beatriz, Morales-Luna, Laura, Ortega-Cuellar, Daniel, Gonzalez-Valdez, Abigail, Arreguin-Espinosa, Roberto, Rufino-Gonzalez, Yadira, Calderon-Jaimes, Ernesto, Castillo-Rodriguez, Rosa Angelica, Wong-Baeza, Carlos, Baeza-Ramirez, Isabel, Pérez de la Cruz V., Vidal-Limon, Abraham, Gomez-Manzo, Saul
Publicada:
1 jul 2023
Resumen:
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.
Filiaciones:
Martinez-Rosas, Victor:
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
Hernandez-Ochoa, Beatriz:
Laboratorio de Inmunoquímica, Hospital Infantil de México Federico Gómez, Secretaría de Salud, Mexico City, 06720, Mexico
Morales-Luna, Laura:
Laboratorio de Bioquímica Genética, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City, 04530, Mexico
Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico
Ortega-Cuellar, Daniel:
Laboratorio de Nutrición Experimental, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City, 04530, Mexico
Gonzalez-Valdez, Abigail:
Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico
Arreguin-Espinosa, Roberto:
Departamento de Química de Biomacromoléculas, Instituto de Química, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico
Rufino-Gonzalez, Yadira:
Laboratorio de Parasitología Experimental, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City, 04530, Mexico
Calderon-Jaimes, Ernesto:
Laboratorio de Inmunoquímica, Hospital Infantil de México Federico Gómez, Secretaría de Salud, Mexico City, 06720, Mexico
Castillo-Rodriguez, Rosa Angelica:
CICATA Unidad Morelos, Instituto Politécnico Nacional, Boulevard de la Tecnología, 1036 Z-1, P 2/2, Atlacholoaya, 62790, Mexico
Wong-Baeza, Carlos:
Laboratorio de Biomembranas, Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, 11340, Mexico
Baeza-Ramirez, Isabel:
Laboratorio de Biomembranas, Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, 11340, Mexico
Pérez de la Cruz V.:
Neurobiochemistry and Behavior Laboratory, National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez”, Mexico City, 14269, Mexico
Vidal-Limon, Abraham:
Red de Estudios Moleculares Avanzados, Clúster Científico y Tecnológico BioMimic®, Instituto de Ecología A.C. (INECOL), Carretera Antigua a Coatepec 351, El Haya, Xalapa, 91073, Mexico
Gomez-Manzo, Saul:
Laboratorio de Bioquímica Genética, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City, 04530, Mexico
gold, All Open Access; Gold
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