Novel giardicidal compounds bearing proton pump inhibitor scaffold proceeding through triosephosphate isomerase inactivation

Scientific Reports
Beatriz Hernández-OchoaHoracio Reyes-Vivas

Abstract

Giardiasis is a worldwide parasitic disease that affects mainly children and immunosuppressed people. Side effects and the emergence of resistance over current used drugs make imperative looking for new antiparasitics through discovering of new biological targets and designing of novel drugs. Recently, it has determined that gastric proton-pump inhibitors (PPI) have anti-giardiasic activity. The glycolytic enzyme, triosephosphate isomerase (GlTIM), is one of its potential targets. Therefore, we employed the scaffold of PPI to design new compounds aimed to increase their antigiardial capacity by inactivating GlTIM. Here we demonstrated that two novel PPI-derivatives (BHO2 and BHO3), have better anti-giardiasic activity than omeprazole in concentrations around 120-130 µM, without cytotoxic effect on mammal cell cultures. The derivatives inactivated GlTIM through the chemical modification of Cys222 promoting local structural changes in the enzyme. Furthermore, derivatives forms adducts linked to Cys residues through a C-S bond. We demonstrated that PPI can be used as scaffolds to design better antiparasitic molecules; we also are proposing a molecular mechanism of reaction for these novel derivatives.

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Citations

Feb 16, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Genaro Rocha-GarduñoGabriel Navarrete-Vázquez
Sep 5, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Beatriz Hernández-OchoaErnesto Calderón-Jaimes
Dec 29, 2020·European Journal of Medicinal Chemistry·Jaime Pérez-VillanuevaOlivia Soria-Arteche
Dec 22, 2020·Biochimica Et Biophysica Acta. General Subjects·Edson Jiovany Ramírez-NavaSaúl Gómez-Manzo
Sep 2, 2020·Journal of Medicinal Chemistry·Andrew RichesTina S Skinner-Adams

Methods Mentioned

BETA
chemical modification
NMR
circular dichroism
size exclusion chromatography
gel filtration

Related Concepts

Schizonticides
Giardia
Giardiasis
Omeprazole magnesium
Triose-Phosphate Isomerase
Protozoan Proteins
Helminth Drug Sensitivity Tests
Proton Pump Inhibitors
Analogs & derivatives
Cell Culture Techniques

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