Recent metabolomic developments for antimalarial drug discovery

Mamede, Lúcia Cristina Coelho Cristino; Schoumacher, Matthieu; Ledoux, Allison; Tullio, Pascal De; Quetin-Leclercq, Joëlle; Frédérich, Michel

doi:10.1007/s00436-022-07673-7

Cited by 5 publications

(7 citation statements)

References 133 publications

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“…When parasites are under significant stress and cannot compensate, cascading reactions that affect multiple systems including metabolic pathways occur [ 46 ]. Given the considerable inhibitory effect of ATS on the glycolytic pathway of parasites and the interference of ATS with various physiological processes of parasites, we next investigated the impact of ATS on the metabolome of parasites using untargeted metabolomics analysis (Figure 7A ).…”

Section: Resultsmentioning

confidence: 99%

Photoaffinity probe‐based antimalarial target identification of artemisinin in the intraerythrocytic developmental cycle of Plasmodium falciparum

Gao,

Wang,

Qiu

et al. 2024

iMeta

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Malaria continues to pose a serious global health threat, and artemisinin remains the core drug for global malaria control. However, the situation of malaria resistance has become increasingly severe due to the emergence and spread of artemisinin resistance. In recent years, significant progress has been made in understanding the mechanism of action (MoA) of artemisinin. Prior research on the MoA of artemisinin mainly focused on covalently bound targets that are alkylated by artemisinin‐free radicals. However, less attention has been given to the reversible noncovalent binding targets, and there is a paucity of information regarding artemisinin targets at different life cycle stages of the parasite. In this study, we identified the protein targets of artemisinin at different stages of the parasite's intraerythrocytic developmental cycle using a photoaffinity probe. Our findings demonstrate that artemisinin interacts with parasite proteins in vivo through both covalent and noncovalent modes. Extensive mechanistic studies were then conducted by integrating target validation, phenotypic studies, and untargeted metabolomics. The results suggest that protein synthesis, glycolysis, and oxidative homeostasis are critically involved in the antimalarial activities of artemisinin. In summary, this study provides fresh insights into the mechanisms underlying artemisinin's antimalarial effects and its protein targets.

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Section: Resultsmentioning

confidence: 99%

Photoaffinity probe‐based antimalarial target identification of artemisinin in the intraerythrocytic developmental cycle of Plasmodium falciparum

Gao,

Wang,

Qiu

et al. 2024

iMeta

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“…MMV000634 could form interactions with amino acid residues of the AdFUEBP homology model, including hydrophobic interactions and hydrogen bonds. From previous studies, MMV000634 (PubChem CID 16018313; Kim et al, 2021) showed antiplasmodial activity with IC50 at 0.56 μM against the trophozoite stage (PubChem Bioassay AID 1189127) via the alpha‐linolenic acid pathway in lipid metabolism (Mamede et al, 2022). This compound might be able to inhibit the activity of AdFUEBP to hamper Plasmodium development in Anopheles mosquitoes.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of Anopheles dirus far upstream element‐binding protein gene lower oocyst numbers of Plasmodium vivax

Kubera

Putanyawiwat

Bantuchai

et al. 2023

Medical Vet Entomology

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The modulation of gene expression levels of Anopheles dirus on Plasmodium vivax infection at the ookinete and oocyst stages was previously reported. In the present study, several upregulated An. dirus genes were selected based on their high expression levels and subcellular locations to examine their roles in P. vivax infection. Five An. dirus genes—carboxylesterase, cuticular protein RR‐2 family, far upstream element‐binding protein, kraken, and peptidase212—were knocked down by dsRNA feeding using dsRNA‐lacZ as a control. The dsRNA‐fed mosquitoes were later challenged by P. vivax–infected blood, and the oocyst numbers were determined. The expression of these five genes was examined in many organs of both male and female mosquitoes. The results showed that the decreased expression level of the far upstream element‐binding protein gene could lower the oocyst numbers, whereas the others showed no effect on P. vivax infection. The expression levels of these genes in ovaries were found, and in many organs, they were similar between male and female mosquitoes. The reduction of these five gene expressions did not affect the lifespan of the mosquitoes. In addition, the malaria box compound, MMV000634, demonstrated the lowest binding energy to the far upstream element‐binding protein using virtual screening. This protein might be a target to block malaria transmission.

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“…Not only are the workflow stages relatively uniform, but so are the extraction methods and solvents, including the data acquisition methods (Vincent & Barrett, 2015). The methods explored in this protocol have generally been used to study other pathogens as well, with differences pertaining to handling the culture, sampling, and data interpretation (Fall et al., 2022; Kafsack & Llinás, 2010; Mamede et al., 2022; Vincent & Barrett, 2015). Metabolomics as an approach is useful regardless of the parasite being studied, and needs only to be adapted to their lifeform, stage, number, and culture conditions.…”

Section: Introductionmentioning

confidence: 99%

Comparison of Three Widely Employed Extraction Methods for Metabolomic Analysis of Trypanosoma brucei

Fall,

Desmet,

Mamede

et al. 2024

Current Protocols

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Trypanosoma brucei (Tb) is the causative agent of human African trypanosomiasis (HAT), also known as sleeping sickness, which can be fatal if left untreated. An understanding of the parasite's cellular metabolism is vital for the discovery of new antitrypanosomal drugs and for disease eradication. Metabolomics can be used to analyze numerous metabolic pathways described as essential to Tb. brucei but has some limitations linked to the metabolites’ physicochemical properties and the extraction process. To develop an optimized method for extracting and analyzing Tb. brucei metabolites, we tested the three most commonly used extraction methods, analyzed the extracts by hydrophilic interaction liquid chromatography high‐resolution mass spectrometry (HILIC LC‐HRMS), and further evaluated the results using quantitative criteria including the number, intensity, reproducibility, and variability of features, as well as qualitative criteria such as the specific coverage of relevant metabolites. Here, we present the resulting protocols for untargeted metabolomic analysis of Tb. brucei using (HILIC LC‐HRMS). © 2024 Wiley Periodicals LLC.Basic Protocol 1: Culture of Trypanosoma brucei brucei parasitesBasic Protocol 2: Preparation of samples for metabolomic analysis of Trypanosoma brucei bruceiBasic Protocol 3: LC‐HRMS‐based metabolomic data analysis of Trypanosoma brucei brucei

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Recent metabolomic developments for antimalarial drug discovery

Cited by 5 publications

References 133 publications

Photoaffinity probe‐based antimalarial target identification of artemisinin in the intraerythrocytic developmental cycle of Plasmodium falciparum

Photoaffinity probe‐based antimalarial target identification of artemisinin in the intraerythrocytic developmental cycle of Plasmodium falciparum

Knockdown of Anopheles dirus far upstream element‐binding protein gene lower oocyst numbers of Plasmodium vivax

Comparison of Three Widely Employed Extraction Methods for Metabolomic Analysis of Trypanosoma brucei

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