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

Abstract 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 l...

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Autores principales:	Wei Mao, Pierre Daligaux, Noureddine Lazar, Tâp Ha-Duong, Christian Cavé, Herman van Tilbeurgh, Philippe M. Loiseau, Sébastien Pomel
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/57cb12b8813340a39e6e047dedf57436
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spelling	oai:doaj.org-article:57cb12b8813340a39e6e047dedf574362021-12-02T11:51:12ZBiochemical analysis of leishmanial and human GDP-Mannose Pyrophosphorylases and selection of inhibitors as new leads10.1038/s41598-017-00848-82045-2322https://doaj.org/article/57cb12b8813340a39e6e047dedf574362017-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00848-8https://doaj.org/toc/2045-2322Abstract 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.Wei MaoPierre DaligauxNoureddine LazarTâp Ha-DuongChristian CavéHerman van TilbeurghPhilippe M. LoiseauSébastien PomelNature 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 Wei Mao Pierre Daligaux Noureddine Lazar Tâp Ha-Duong Christian Cavé Herman van Tilbeurgh Philippe M. Loiseau Sébastien Pomel Biochemical analysis of leishmanial and human GDP-Mannose Pyrophosphorylases and selection of inhibitors as new leads
description	Abstract 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.
format	article
author	Wei Mao Pierre Daligaux Noureddine Lazar Tâp Ha-Duong Christian Cavé Herman van Tilbeurgh Philippe M. Loiseau Sébastien Pomel
author_facet	Wei Mao Pierre Daligaux Noureddine Lazar Tâp Ha-Duong Christian Cavé Herman van Tilbeurgh Philippe M. Loiseau Sébastien Pomel
author_sort	Wei Mao
title	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_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_sort	biochemical analysis of leishmanial and human gdp-mannose pyrophosphorylases and selection of inhibitors as new leads
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/57cb12b8813340a39e6e047dedf57436
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Biochemical analysis of leishmanial and human GDP-Mannose Pyrophosphorylases and selection of inhibitors as new leads

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