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Biochemical analysis of leishmanial and human GDP-Mannose Pyrophosphorylases and selection of inhibitors as new leads

Leishmaniases are an ensemble of diseases caused by the protozoan parasite of the genus Leishmania. Current antileishmanial treatments are limited and present main issues of toxicity and drug resistance emergence. Therefore, the generation of new inhibitors specifically directed against a leishmania...

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Autores principales: Mao, Wei, Daligaux, Pierre, Lazar, Noureddine, Ha-Duong, Tâp, Cavé, Christian, van Tilbeurgh, Herman, Loiseau, Philippe M., Pomel, Sébastien
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5429698/
https://www.ncbi.nlm.nih.gov/pubmed/28389670
http://dx.doi.org/10.1038/s41598-017-00848-8
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author Mao, Wei
Daligaux, Pierre
Lazar, Noureddine
Ha-Duong, Tâp
Cavé, Christian
van Tilbeurgh, Herman
Loiseau, Philippe M.
Pomel, Sébastien
author_facet Mao, Wei
Daligaux, Pierre
Lazar, Noureddine
Ha-Duong, Tâp
Cavé, Christian
van Tilbeurgh, Herman
Loiseau, Philippe M.
Pomel, Sébastien
author_sort Mao, Wei
collection PubMed
description Leishmaniases are an ensemble of diseases caused by the protozoan parasite of the genus Leishmania. Current antileishmanial treatments are limited and present main issues of toxicity and drug resistance emergence. Therefore, the generation of new inhibitors specifically directed against a leishmanial target is an attractive strategy to expand the chemotherapeutic arsenal. GDP-Mannose Pyrophosphorylase (GDP-MP) is a prominent therapeutic target involved in host-parasite recognition which has been described to be essential for parasite survival. In this work, we produced and purified GDP-MPs from L. mexicana (LmGDP-MP), L. donovani (LdGDP-MP), and human (hGDP-MP), and compared their enzymatic properties. From a rationale design of 100 potential inhibitors, four compounds were identified having a promising and specific inhibitory effect on parasite GDP-MP and antileishmanial activities, one of them exhibits a competitive inhibition on LdGDP-MP and belongs to the 2-substituted quinoline series.
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spelling pubmed-54296982017-05-15 Biochemical analysis of leishmanial and human GDP-Mannose Pyrophosphorylases and selection of inhibitors as new leads Mao, Wei Daligaux, Pierre Lazar, Noureddine Ha-Duong, Tâp Cavé, Christian van Tilbeurgh, Herman Loiseau, Philippe M. Pomel, Sébastien Sci Rep Article Leishmaniases are an ensemble of diseases caused by the protozoan parasite of the genus Leishmania. Current antileishmanial treatments are limited and present main issues of toxicity and drug resistance emergence. Therefore, the generation of new inhibitors specifically directed against a leishmanial target is an attractive strategy to expand the chemotherapeutic arsenal. GDP-Mannose Pyrophosphorylase (GDP-MP) is a prominent therapeutic target involved in host-parasite recognition which has been described to be essential for parasite survival. In this work, we produced and purified GDP-MPs from L. mexicana (LmGDP-MP), L. donovani (LdGDP-MP), and human (hGDP-MP), and compared their enzymatic properties. From a rationale design of 100 potential inhibitors, four compounds were identified having a promising and specific inhibitory effect on parasite GDP-MP and antileishmanial activities, one of them exhibits a competitive inhibition on LdGDP-MP and belongs to the 2-substituted quinoline series. Nature Publishing Group UK 2017-04-07 /pmc/articles/PMC5429698/ /pubmed/28389670 http://dx.doi.org/10.1038/s41598-017-00848-8 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Mao, Wei
Daligaux, Pierre
Lazar, Noureddine
Ha-Duong, Tâp
Cavé, Christian
van Tilbeurgh, Herman
Loiseau, Philippe M.
Pomel, Sébastien
Biochemical analysis of leishmanial and human GDP-Mannose Pyrophosphorylases and selection of inhibitors as new leads
title Biochemical analysis of leishmanial and human GDP-Mannose Pyrophosphorylases and selection of inhibitors as new leads
title_full Biochemical analysis of leishmanial and human GDP-Mannose Pyrophosphorylases and selection of inhibitors as new leads
title_fullStr Biochemical analysis of leishmanial and human GDP-Mannose Pyrophosphorylases and selection of inhibitors as new leads
title_full_unstemmed Biochemical analysis of leishmanial and human GDP-Mannose Pyrophosphorylases and selection of inhibitors as new leads
title_short Biochemical analysis of leishmanial and human GDP-Mannose Pyrophosphorylases and selection of inhibitors as new leads
title_sort biochemical analysis of leishmanial and human gdp-mannose pyrophosphorylases and selection of inhibitors as new leads
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5429698/
https://www.ncbi.nlm.nih.gov/pubmed/28389670
http://dx.doi.org/10.1038/s41598-017-00848-8
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