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

International journal of molecular sciences, 2023-07, Vol.24 (14) [Peer Reviewed Journal]

COPYRIGHT 2023 MDPI AG ;ISSN: 1422-0067 ;EISSN: 1422-0067 ;DOI: 10.3390/ijms241411516

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  • Title:
    Nitazoxanide Inhibits the Bifunctional Enzyme GlG6PD::6PGL of IGiardia lamblia/I: Biochemical and In Silico Characterization of a New Druggable Target
  • Author: Martínez-Rosas, Víctor ; Hernández-Ochoa, Beatriz ; Morales-Luna, Laura ; Ortega-Cuellar, Daniel ; González-Valdez, Abigail ; Arreguin-Espinosa, Roberto ; Rufino-González, Yadira ; Calderón-Jaimes, Ernesto ; Castillo-Rodríguez, Rosa Angélica ; Wong-Baeza, Carlos ; Baeza-Ramírez, Isabel ; Pérez de la Cruz, Verónica ; Vidal-Limón, Abraham ; Gómez-Manzo, Saúl
  • Subjects: Enzymes
  • Is Part Of: International journal of molecular sciences, 2023-07, Vol.24 (14)
  • Description: 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[sup.+] binding site. The findings of this study provide a novel mechanistic basis and strategy for the antigiardial activity of the NTZ drug.
  • Publisher: MDPI AG
  • Language: English
  • Identifier: ISSN: 1422-0067
    EISSN: 1422-0067
    DOI: 10.3390/ijms241411516
  • Source: PubMed Central
    ProQuest Central
    DOAJ Directory of Open Access Journals
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