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

Pomel, Sébastien; Mao, Wenfei; Ha-Duong, Tâp; Cavé, Christian; Loiseau, Philippe M.

doi:10.3389/fcimb.2019.00186

Cited by 9 publications

(7 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…GDP-Mannose Pyrophosphorylase (GDP-MP) is an enzyme involved in host–parasite recognition considered to be essential for parasite infection [ 83 , 84 ]. GDP-MPs were purified from L. mexicana ( Lm GDP-MP) and L. donovani ( Ld GDP-MP), and their enzymatic properties were compared with the human enzyme ( h GDP-MP) [ 60 , 85 , 86 , 87 ]. From a rationale design strategy including molecular modeling of 100 potential inhibitors, four compounds were identified as having a promising and specific inhibitory effect on parasite GDP-MP associated with antileishmanial activity.…”

Section: The Potential Of 2-substituted Quinolines As Antileishmanial...mentioning

confidence: 99%

The Potential of 2-Substituted Quinolines as Antileishmanial Drug Candidates

et al. 2022

Self Cite

View full text Add to dashboard Cite

There is a need for new, cost-effective drugs to treat leishmaniasis. A strategy based on traditional medicine practiced in Bolivia led to the discovery of the 2-substituted quinoline series as a source of molecules with antileishmanial activity and low toxicity. This review documents the development of the series from the first isolated natural compounds through several hundred synthetized molecules to an optimized compound exhibiting an in vitro IC50 value of 0.2 µM against Leishmania donovani, and a selectivity index value of 187, together with in vivo activity on the L. donovani/hamster model. Attempts to establish structure–activity relationships are described, as well as studies that have attempted to determine the mechanism of action. For the latter, it appears that molecules of this series act on multiple targets, possibly including the immune system, which could explain the observed lack of drug resistance after in vitro drug pressure. We also show how nanotechnology strategies could valorize these drugs through adapted formulations and how a mechanistic targeting approach could generate new compounds with increased activity.

show abstract

Section: The Potential Of 2-substituted Quinolines As Antileishmanial...mentioning

confidence: 99%

The Potential of 2-Substituted Quinolines as Antileishmanial Drug Candidates

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…Recombinant GDP-MPs from two geographically distant Leishmania species, L. donovani (LdGDP-MP) and L. mexicana (LmGDP-MP), and from human (hGDP-MP) have been previously expressed, produced, and purified, and their enzymatic properties have been characterized [16,17]. In the present work, we purified a third leishmanial GDP-MP, called LiGDP-MP, from the species L. infantum, presenting a unique amino acid difference with LdGDP-MP.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…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. In this pathway, the formation of GDP-mannose is catalyzed by the GDP-Mannose Pyrophosphorylase (GDP-MP) from the substrates mannose-1-phosphate and GTP [ 6 ]. A knockout in L. mexicana demonstrated that GDP-MP is essential for amastigote survival both in vitro and in vivo [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

Self Cite

View full text Add to dashboard Cite

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.

show abstract

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

Cited by 9 publications

References 60 publications

The Potential of 2-Substituted Quinolines as Antileishmanial Drug Candidates

The Potential of 2-Substituted Quinolines as Antileishmanial Drug Candidates

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

Contact Info

Product

Resources

About