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

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 drug...

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Autores principales:	B. Hernández-Ochoa, G. Navarrete-Vázquez, C. Nava-Zuazo, A. Castillo-Villanueva, S. T. Méndez, A. Torres-Arroyo, S. Gómez-Manzo, J. Marcial-Quino, M. Ponce-Macotela, Y. Rufino-González, M. Martínez-Gordillo, G. Palencia-Hernández, N. Esturau-Escofet, E. Calderon-Jaimes, J. Oria-Hernández, H. Reyes-Vivas
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a2e2eb22efc4463c908cf0ac908341c3
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spelling	oai:doaj.org-article:a2e2eb22efc4463c908cf0ac908341c32021-12-02T12:32:31ZNovel giardicidal compounds bearing proton pump inhibitor scaffold proceeding through triosephosphate isomerase inactivation10.1038/s41598-017-07612-y2045-2322https://doaj.org/article/a2e2eb22efc4463c908cf0ac908341c32017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-07612-yhttps://doaj.org/toc/2045-2322Abstract 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.B. Hernández-OchoaG. Navarrete-VázquezC. Nava-ZuazoA. Castillo-VillanuevaS. T. MéndezA. Torres-ArroyoS. Gómez-ManzoJ. Marcial-QuinoM. Ponce-MacotelaY. Rufino-GonzálezM. Martínez-GordilloG. Palencia-HernándezN. Esturau-EscofetE. Calderon-JaimesJ. Oria-HernándezH. Reyes-VivasNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q B. Hernández-Ochoa G. Navarrete-Vázquez C. Nava-Zuazo A. Castillo-Villanueva S. T. Méndez A. Torres-Arroyo S. Gómez-Manzo J. Marcial-Quino M. Ponce-Macotela Y. Rufino-González M. Martínez-Gordillo G. Palencia-Hernández N. Esturau-Escofet E. Calderon-Jaimes J. Oria-Hernández H. Reyes-Vivas Novel giardicidal compounds bearing proton pump inhibitor scaffold proceeding through triosephosphate isomerase inactivation
description	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.
format	article
author	B. Hernández-Ochoa G. Navarrete-Vázquez C. Nava-Zuazo A. Castillo-Villanueva S. T. Méndez A. Torres-Arroyo S. Gómez-Manzo J. Marcial-Quino M. Ponce-Macotela Y. Rufino-González M. Martínez-Gordillo G. Palencia-Hernández N. Esturau-Escofet E. Calderon-Jaimes J. Oria-Hernández H. Reyes-Vivas
author_facet	B. Hernández-Ochoa G. Navarrete-Vázquez C. Nava-Zuazo A. Castillo-Villanueva S. T. Méndez A. Torres-Arroyo S. Gómez-Manzo J. Marcial-Quino M. Ponce-Macotela Y. Rufino-González M. Martínez-Gordillo G. Palencia-Hernández N. Esturau-Escofet E. Calderon-Jaimes J. Oria-Hernández H. Reyes-Vivas
author_sort	B. Hernández-Ochoa
title	Novel giardicidal compounds bearing proton pump inhibitor scaffold proceeding through triosephosphate isomerase inactivation
title_short	Novel giardicidal compounds bearing proton pump inhibitor scaffold proceeding through triosephosphate isomerase inactivation
title_full	Novel giardicidal compounds bearing proton pump inhibitor scaffold proceeding through triosephosphate isomerase inactivation
title_fullStr	Novel giardicidal compounds bearing proton pump inhibitor scaffold proceeding through triosephosphate isomerase inactivation
title_full_unstemmed	Novel giardicidal compounds bearing proton pump inhibitor scaffold proceeding through triosephosphate isomerase inactivation
title_sort	novel giardicidal compounds bearing proton pump inhibitor scaffold proceeding through triosephosphate isomerase inactivation
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/a2e2eb22efc4463c908cf0ac908341c3
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Novel giardicidal compounds bearing proton pump inhibitor scaffold proceeding through triosephosphate isomerase inactivation

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