GDP‐Mannose: A Key Point for Target Identification and Drug Design in Kinetoplastids

Pomel, Sébastien; Loiseau, Philippe M.

doi:10.1002/9783527670383.ch17

Cited by 4 publications

(4 citation statements)

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“…As host- Leishmania interactions mainly rely on glycoconjugate recognition, an inhibition of glycoconjugate biosynthesis could affect this molecular recognition, and therefore reduce parasite burden. Furthermore, as the glycosylation is a crucial pathway for macrophage infection (Descoteaux et al, 1995; Descoteaux and Turco, 1999; Pomel and Loiseau, 2013; Podinovskaia and Descoteaux, 2015), we hypothesize that an alteration of glycoconjugate structures would not easily select drug resistance.…”

Section: Targeting Membrane Glycoconjugate Metabolismmentioning

confidence: 96%

“…Mannose-containing glycoconjugates represent a large proportion of the carbohydrates addressed at the surface of a eukaryotic cell and are involved in many biological processes such as intercellular recognition, adhesion or signaling (Varki, 2007; Colley et al, 2017). In Leishmania , a wide range of unusual mannose-containing glycoconjugates [e.g., GlycosylPhosphatidylInositol (GPI) anchors, LipoPhosphoGlycans (LPG), ProteoPhosphoGlycans (PPG) or GlycosylInositolPhosphoLipids (GIPLs)] are synthesized and are essential for parasite virulence (Descoteaux and Turco, 1999; Pomel and Loiseau, 2013). The biosynthesis of these glycoconjugates requires initially the conversion of mannose into GDP-mannose.…”

Section: Targeting Membrane Glycoconjugate Metabolismmentioning

confidence: 99%

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GDP-Mannose Pyrophosphorylase: A Biologically Validated Target for Drug Development Against Leishmaniasis

Pomel

Mao

Ha-Duong

et al. 2019

Front. Cell. Infect. Microbiol.

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Leishmaniases are neglected tropical diseases that threaten about 350 million people in 98 countries around the world. In order to find new antileishmanial drugs, an original approach consists in reducing the pathogenic effect of the parasite by impairing the glycoconjugate biosynthesis, necessary for parasite recognition and internalization by the macrophage. Some proteins appear to be critical in this way, and one of them, the GDP-Mannose Pyrophosphorylase (GDP-MP), is an attractive target for the design of specific inhibitors as it is essential for Leishmania survival and it presents significant differences with the host counterpart. Two GDP-MP inhibitors, compounds A and B , have been identified in two distinct studies by high throughput screening and by a rational approach based on molecular modeling, respectively. Compound B was found to be the most promising as it exhibited specific competitive inhibition of leishmanial GDP-MP and antileishmanial activities at the micromolar range with interesting selectivity indexes, as opposed to compound A . Therefore, compound B can be used as a pharmacological tool for the development of new specific antileishmanial drugs.

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Section: Targeting Membrane Glycoconjugate Metabolismmentioning

confidence: 96%

Section: Targeting Membrane Glycoconjugate Metabolismmentioning

confidence: 99%

GDP-Mannose Pyrophosphorylase: A Biologically Validated Target for Drug Development Against Leishmaniasis

Pomel

Mao

Ha-Duong

et al. 2019

Front. Cell. Infect. Microbiol.

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“…The GDP-mannose pyrophosphorylase (GDP-MP) is a ubiquitous glycosylation enzyme catalyzing the formation of GDP-mannose from mannose-1-phosphate (Man-1-P) and GTP [7]. In Leishmania, this nucleotide-sugar is an activated form of mannose used to biosynthesize a wide range of glycoconjugates, such as LipoPhosGhoglycan (LPG), ProteoPhosphoGlycan (PPG), or GlycosylPhosphatidylInositol (GPI), which are essential for host-cell recognition [8]. A knockout of the gene encoding for GDP-MP in L. mexicana led to perturbed morphology and cytokinesis and to retarded growth in the promastigote form, and to a lack of development and rapid elimination of the amastigote form within the macrophage [9,10].…”

Section: Introductionmentioning

confidence: 99%

Minor Impact of A258D Mutation on Biochemical and Enzymatic Properties of Leishmania infantum GDP-Mannose Pyrophosphorylase

et al. 2022

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Background: Leishmaniasis, a vector-borne disease caused by the protozoan parasite from the genus Leishmania, is endemic to tropical and subtropical areas. Few treatments are available against leishmaniasis, with all presenting issues of toxicity, resistance, and/or cost. In this context, the development of new antileishmanial drugs is urgently needed. GDP-mannose pyrophosphorylase (GDP-MP), an enzyme involved in the mannosylation pathway, has been described to constitute an attractive therapeutic target for the development of specific antileishmanial agents. Methods: In this work, we produced, purified, and analyzed the enzymatic properties of the recombinant L. infantum GDP-MP (LiGDP-MP), a single leishmanial GDP-MP that presents mutation of an aspartate instead of an alanine at position 258, which is also the single residue difference with the homolog in L. donovani: LdGDP-MP. Results: The purified LiGDP-MP displayed high substrate and cofactor specificities, a sequential random mechanism of reaction, and the following kinetic constants: Vm at 0.6 µM·min−1, Km from 15–18 µM, kcat from 12.5–13 min−1, and kcat/Km at around 0.8 min−1µM−1. Conclusions: These results show that LiGDP-MP has similar biochemical and enzymatic properties to LdGDP-MP. Further studies are needed to determine the advantage for L. infantum of the A258D residue change in GDP-MP.

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“…The surface of Leishmania is composed of many mannose-containing glycoconjugates, such as lipophosphoglycans, proteophosphoglycans, glycosylinositolphospholipids, or glycosylphosphatidylinositol, which are essential for host cell recognition [ 4 , 5 ]. The mannosylation pathway requires the conversion of mannose into a nucleotide sugar, GDP-mannose, which is further used as a substrate by mannosyltransferases to transfer mannose on growing glycoconjugates.…”

Section: Introductionmentioning

confidence: 99%

Alkyl-Resorcinol Derivatives as Inhibitors of GDP-Mannose Pyrophosphorylase with Antileishmanial Activities

et al. 2021

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Leishmaniasis is a vector-borne disease caused by the protozoan parasite Leishmania found in tropical and sub-tropical areas, affecting 12 million people around the world. Only few treatments are available against this disease and all of them present issues of toxicity and/or resistance. In this context, the development of new antileishmanial drugs specifically directed against a therapeutic target appears to be a promising strategy. The GDP-Mannose Pyrophosphorylase (GDP-MP) has been previously shown to be an attractive therapeutic target in Leishmania. In this study, a chemical library of 5000 compounds was screened on both L. infantum (LiGDP-MP) and human (hGDP-MP) GDP-MPs. From this screening, oncostemonol D was found to be active on both GDP-MPs at the micromolar level. Ten alkyl-resorcinol derivatives, of which oncostemonols E and J (2 and 3) were described for the first time from nature, were then evaluated on both enzymes as well as on L. infantum axenic and intramacrophage amastigotes. From this evaluation, compounds 1 and 3 inhibited both GDP-MPs at the micromolar level, and compound 9 displayed a three-times lower IC50 on LiGDP-MP, at 11 µM, than on hGDP-MP. As they displayed mild activities on the parasite, these compounds need to be further pharmacomodulated in order to improve their affinity and specificity to the target as well as their antileishmanial activity.

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GDP‐Mannose: A Key Point for Target Identification and Drug Design in Kinetoplastids

Cited by 4 publications

References 94 publications

GDP-Mannose Pyrophosphorylase: A Biologically Validated Target for Drug Development Against Leishmaniasis

GDP-Mannose Pyrophosphorylase: A Biologically Validated Target for Drug Development Against Leishmaniasis

Minor Impact of A258D Mutation on Biochemical and Enzymatic Properties of Leishmania infantum GDP-Mannose Pyrophosphorylase

Alkyl-Resorcinol Derivatives as Inhibitors of GDP-Mannose Pyrophosphorylase with Antileishmanial Activities

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