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      In silico analysis of a therapeutic target in Leishmania infantum: the guanosine-diphospho-D-mannose pyrophosphorylase Translated title: Analyse in silico d’une cible thérapeutique chez Leishmania infantum : la guanosine-diphospho-D-mannose pyrophosphorylase

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          Abstract

          Leishmaniases are tropical and sub-tropical diseases for which classical drugs ( i.e. antimonials) exhibit toxicity and drug resistance. Such a situation requires to find new chemical series with antileishmanial activity. This work consists in analyzing the structure of a validated target in Leishmania: the GDP-mannose pyrophosphorylase (GDP-MP), an enzyme involved in glycosylation and essential for amastigote survival. By comparing both human and L. infantum GDP-MP 3D homology models, we identified (i) a common motif of amino acids that binds to the mannose moiety of the substrate and, interestingly, (ii) a motif that is specific to the catalytic site of the parasite enzyme. This motif could then be used to design compounds that specifically inhibit the leishmanial GDP-MP, without any effect on the human homolog.

          Translated abstract

          Les leishmanioses sont des parasitoses tropicales et subtropicales pour lesquelles les traitements classiques ( i.e. antimoniés) sont toxiques et présentent des problèmes de résistance. Dans ce contexte, il est nécessaire de trouver de nouvelles séries chimiques ayant une activité antileishmanienne. Ce travail consiste à analyser la structure d’une cible validée chez Leishmania : la GDP-mannose pyrophosphorylase (GDP-MP), une enzyme impliquée dans la glycosylation et essentielle à la survie du stade amastigote. En comparant les modèles 3D par homologie des GDP-MP humaine et de L. infantum, nous avons identifié (i) un motif d’acides aminés commun qui interagit avec la partie mannose du substrat et (ii) un motif spécifique au site catalytique de l’enzyme du parasite. Ce motif pourrait être utilisé pour concevoir des composés qui inhibent spécifiquement la GDP-MP leishmanienne, tout en n’ayant aucun effet sur l’homologue humaine.

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          Most cited references 7

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          Glycan-based interactions involving vertebrate sialic-acid-recognizing proteins.

           Ajit Varki (2007)
          All cells in nature are covered by a dense and complex array of carbohydrates. Given their prominence on cell surfaces, it is not surprising that these glycans mediate and/or modulate many cellular interactions. Proteins that bind sialic acid, a sugar that is found on the surface of the cell and on secreted proteins in vertebrates, are involved in a broad range of biological processes, including intercellular adhesion, signalling and microbial attachment. Studying the roles of such proteins in vertebrates has improved our understanding of normal physiology, disease and human evolution.
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            Glycoconjugates in Leishmania infectivity.

             S Turco,  A Descoteaux (1999)
            Leishmaniasis is a major health problem to humans and is caused by one of the world's major pathogens, the Leishmania parasite. These protozoa have the remarkable ability to avoid destruction in hostile environments they encounter throughout their life cycle. That Leishmania parasites have adapted to not only survive, but to proliferate largely is due to the protection conferred by unique glycoconjugates that are either on the parasites' cell surface or secreted. Most of these specialized molecules are members of a family of phosphoglycans while others are a family of glycosylinositol phospholipids. Together they have been implicated in a surprisingly large number of functions for the parasites throughout their life cycle and, therefore, are key players in their pathogenesis. This review summarizes the biological roles of these glycoconjugates and how they are believed to contribute to Leishmania survival in destructive surroundings.
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              Inhibitors of Leishmania GDP-mannose pyrophosphorylase identified by high-throughput screening of small-molecule chemical library.

              The current treatment for leishmaniasis is based on chemotherapy, which relies on a handful of drugs with serious limitations, such as high cost, toxicity, and a lack of efficacy in regions of endemicity. Therefore, the development of new, effective, and affordable antileishmanial drugs is a global health priority. Leishmania synthesizes a range of mannose-rich glycoconjugates that are essential for parasite virulence and survival. A prerequisite for glycoconjugate biosynthesis is the conversion of monosaccharides to the activated mannose donor, GDP-mannose, the product of a reaction catalyzed by GDP-mannose pyrophosphorylase (GDP-MP). The deletion of the gene encoding GDP-MP in Leishmania led to a total loss of virulence, indicating that the enzyme is an ideal drug target. We developed a phosphate sensor-based high-throughput screening assay to quantify the activity of GDP-MP and screened a library containing approximately 80,000 lead-like compounds for GDP-MP inhibitors. On the basis of their GDP-MP inhibitory properties and chemical structures, the activities of 20 compounds which were not toxic to mammalian cells were tested against ex vivo amastigotes and in macrophage amastigote assays. The most potent compound identified in the primary screen (compound 3), a quinoline derivative, demonstrated dose-dependent activity in both assays (50% inhibitory concentration = 21.9 microM in the macrophage assay) and was shown to be nontoxic to human fibroblasts. In order to elucidate signs of an early structure-activity relationship (SAR) for this class of compounds, we obtained and tested analogues of compound 3 and undertook limited medicinal chemistry optimization, which included the use of a number of SAR probes of the piperazinyl aryl substituent of compound 3. We have identified novel candidate compounds for the design and synthesis of antileishmanial therapeutics.
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                Author and article information

                Journal
                Parasite
                Parasite
                parasite
                Parasite : journal de la Société Française de Parasitologie
                EDP Sciences
                1252-607X
                1776-1042
                February 2012
                15 February 2012
                : 19
                : 1 ( publisher-idID: parasite/2012/01 )
                : 63-70
                Affiliations
                [1 ] Université Paris-Sud 11, Faculté de Pharmacie, UMR 8076 CNRS, Chimiothérapie Antiparasitaire 5, rue Jean-Baptiste Clément 92296 Châtenay-Malabry France
                [2 ] Université Paris-Sud 11, Faculté de Pharmacie, UMR 8076 CNRS, Conception et Synthèse de Molécules à Activité Thérapeutique Châtenay-Malabry Cedex France
                Author notes
                [* ]Correspondence: Philippe Loiseau. Tel.: 33 (0)1 46 83 55 53 – Fax: 33 (0)1 46 83 55 57. E-mail: philippe.loiseau@ 123456u-psud.fr
                Article
                parasite2012191p63 10.1051/parasite/2012191063
                10.1051/parasite/2012191063
                3671423
                22314241
                © PRINCEPS Editions, Paris, 2012

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 5, Tables: 0, Equations: 0, References: 14, Pages: 8
                Categories
                Original Contribution

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