Multilevel Approach for the Treatment of Giardiasis by Targeting Arginine Deiminase
Por:
Fernandez-Lainez, Cynthia, de la Mora-de la Mora, Ignacio, Garcia-Torres, Itzhel, Enriquez-Flores, Sergio, Flores-Lopez, Luis, Gutierrez-Castrellon, Pedro, Yepez-Mulia, Lilian, Matadamas-Martinez, Felix, de Vos, Paul, Lopez-Velazquez, Gabriel
Publicada:
1 sep 2021
Resumen:
Giardiasis represents a latent problem in public health due to the
exceptionally pathogenic strategies of the parasite Giardia lamblia for
evading the human immune system. Strains resistant to first-line drugs
are also a challenge. Therefore, new antigiardial therapies are urgently
needed. Here, we tested giardial arginine deiminase (GlADI) as a target
against giardiasis. GlADI belongs to an essential pathway in Giardia for
the synthesis of ATP, which is absent in humans. In silico docking with
six thiol-reactive compounds was performed; four of which are approved
drugs for humans. Recombinant GlADI was used in enzyme inhibition
assays, and computational in silico predictions and spectroscopic
studies were applied to follow the enzyme's structural disturbance and
identify possible effective drugs. Inhibition by modification of
cysteines was corroborated using Ellman's method. The efficacy of these
drugs on parasite viability was assayed on Giardia trophozoites, along
with the inhibition of the endogenous GlADI. The most potent drug
against GlADI was assayed on Giardia encystment. The tested drugs
inhibited the recombinant GlADI by modifying its cysteines and,
potentially, by altering its 3D structure. Only rabeprazole and
omeprazole decreased trophozoite survival by inhibiting endogenous
GlADI, while rabeprazole also decreased the Giardia encystment rate.
These findings demonstrate the potential of GlADI as a target against
giardiasis.
Filiaciones:
Fernandez-Lainez, Cynthia:
Lopez-Velazquez, G (Corresponding Author), Inst Nacl Pediat, Lab Biomol & Salud Infantil, Ciudad De Mexico 04530, Mexico. Fernandez-Lainez, Cynthia, Inst Nacl Pediat, Lab Errores Innatos Metab & Tamiz, Ciudad De Mexico 04530, Mexico. Fernandez-Lainez, Cynthia
de la Mora-de la Mora, Ignacio:
Lopez-Velazquez, G (Corresponding Author), Inst Nacl Pediat, Lab Biomol & Salud Infantil, Ciudad De Mexico 04530, Mexico. Fernandez-Lainez, Cynthia, Inst Nacl Pediat, Lab Errores Innatos Metab & Tamiz, Ciudad De Mexico 04530, Mexico. Fernandez-Lainez, Cynthia
Garcia-Torres, Itzhel:
Lopez-Velazquez, G (Corresponding Author), Inst Nacl Pediat, Lab Biomol & Salud Infantil, Ciudad De Mexico 04530, Mexico. Fernandez-Lainez, Cynthia, Inst Nacl Pediat, Lab Errores Innatos Metab & Tamiz, Ciudad De Mexico 04530, Mexico. Fernandez-Lainez, Cynthia
Enriquez-Flores, Sergio:
Lopez-Velazquez, G (Corresponding Author), Inst Nacl Pediat, Lab Biomol & Salud Infantil, Ciudad De Mexico 04530, Mexico. Fernandez-Lainez, Cynthia, Inst Nacl Pediat, Lab Errores Innatos Metab & Tamiz, Ciudad De Mexico 04530, Mexico. Fernandez-Lainez, Cynthia
Flores-Lopez, Luis:
Lopez-Velazquez, G (Corresponding Author), Inst Nacl Pediat, Lab Biomol & Salud Infantil, Ciudad De Mexico 04530, Mexico. Fernandez-Lainez, Cynthia, Inst Nacl Pediat, Lab Errores Innatos Metab & Tamiz, Ciudad De Mexico 04530, Mexico. Fernandez-Lainez, Cynthia
Gutierrez-Castrellon, Pedro:
Lopez-Velazquez, G (Corresponding Author), Inst Nacl Pediat, Lab Biomol & Salud Infantil, Ciudad De Mexico 04530, Mexico. Fernandez-Lainez, Cynthia, Inst Nacl Pediat, Lab Errores Innatos Metab & Tamiz, Ciudad De Mexico 04530, Mexico. Fernandez-Lainez, Cynthia
Yepez-Mulia, Lilian:
Lopez-Velazquez, G (Corresponding Author), Inst Nacl Pediat, Lab Biomol & Salud Infantil, Ciudad De Mexico 04530, Mexico. Fernandez-Lainez, Cynthia, Inst Nacl Pediat, Lab Errores Innatos Metab & Tamiz, Ciudad De Mexico 04530, Mexico. Fernandez-Lainez, Cynthia
Matadamas-Martinez, Felix:
Lopez-Velazquez, G (Corresponding Author), Inst Nacl Pediat, Lab Biomol & Salud Infantil, Ciudad De Mexico 04530, Mexico. Fernandez-Lainez, Cynthia, Inst Nacl Pediat, Lab Errores Innatos Metab & Tamiz, Ciudad De Mexico 04530, Mexico. Fernandez-Lainez, Cynthia
de Vos, Paul:
Lopez-Velazquez, G (Corresponding Author), Inst Nacl Pediat, Lab Biomol & Salud Infantil, Ciudad De Mexico 04530, Mexico. Fernandez-Lainez, Cynthia, Inst Nacl Pediat, Lab Errores Innatos Metab & Tamiz, Ciudad De Mexico 04530, Mexico. Fernandez-Lainez, Cynthia
Lopez-Velazquez, Gabriel:
Lopez-Velazquez, G (Corresponding Author), Inst Nacl Pediat, Lab Biomol & Salud Infantil, Ciudad De Mexico 04530, Mexico. Fernandez-Lainez, Cynthia, Inst Nacl Pediat, Lab Errores Innatos Metab & Tamiz, Ciudad De Mexico 04530, Mexico. Fernandez-Lainez, Cynthia
Gold
|