The
 Plasmodium
 Lactate/H
 +
 Transporter PfFNT Is Essential and Druggable
 In Vivo

Davies, Heledd; Bergmann, Bärbel; Walloch, Philipp; Nerlich, C.; Hansen, Christian; Wittlin, Sergio; Spielmann, Tobias; Treeck, Moritz; Beitz, Eric

doi:10.1128/aac.00356-23

Cited by 6 publications

(1 citation statement)

References 35 publications

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“…Conditional knockout demonstrated the essentiality of the pf f nt gene during the blood stage, whereas phenotypic defects were not observed during the sexual development of the parasite. 122 An inhibitor of Pf FNT in this later study was found to possess high potency in P. berghei-and P. falciparum-infected mice, with their in vivo activity profiles being comparable to that of artesunate. Taken together, these data confirmed the validity and druggability of Pf FNT as an antimalarial target.…”

Section: Plasmodium Ispd (2-c-methyl-d-erythritol 4-phosphate Cytidyl...mentioning

confidence: 65%

Emerging Drug Targets for Antimalarial Drug Discovery: Validation and Insights into Molecular Mechanisms of Function

Cheuka,

Njaria,

Mayoka

et al. 2024

J. Med. Chem.

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Approximately 619,000 malaria deaths were reported in 2021, and resistance to recommended drugs, including artemisinin-combination therapies (ACTs), threatens malaria control. Treatment failure with ACTs has been found to be as high as 93% in northeastern Thailand, and parasite mutations responsible for artemisinin resistance have already been reported in some African countries. Therefore, there is an urgent need to identify alternative treatments with novel targets. In this Perspective, we discuss some promising antimalarial drug targets, including enzymes involved in proteolysis, DNA and RNA metabolism, protein synthesis, and isoprenoid metabolism. Other targets discussed are transporters, Plasmodium falciparum acetyl-coenzyme A synthetase, N-myristoyltransferase, and the cyclic guanosine monophosphate-dependent protein kinase G. We have outlined mechanistic details, where these are understood, underpinning the biological roles and hence druggability of such targets. We believe that having a clear understanding of the underlying chemical interactions is valuable to medicinal chemists in their quest to design appropriate inhibitors. ■ SIGNIFICANCEFor the first time, we report some emerging antimalarial targets with special emphasis on mechanistic details of how they function. We believe such details are of value in medicinal chemistry toward facilitating rapid design of inhibitors. While considerable efforts have been made regarding drug target identification, the corresponding medicinal chemistry hit identification and hit-to-lead optimization have been insufficient. We believe this Perspective will contribute to bridging the gap between target discovery and inhibitor design.

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Section: Plasmodium Ispd (2-c-methyl-d-erythritol 4-phosphate Cytidyl...mentioning

confidence: 65%

Emerging Drug Targets for Antimalarial Drug Discovery: Validation and Insights into Molecular Mechanisms of Function

Cheuka,

Njaria,

Mayoka

et al. 2024

J. Med. Chem.

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We are MedChem: The Frontiers in Medicinal Chemistry 2024

Schiedel,

Barbie,

Pape

et al. 2024

ChemMedChem

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The Frontiers in Medicinal Chemistry (FiMC) is the largest international Medicinal Chemistry conference in Germany and took place from March 17th to 20th 2024 in Munich. Co‐organized by the Division of Medicinal Chemistry of the German Chemical Society (Gesellschaft Deutscher Chemiker; GDCh) and the Division of Pharmaceutical and Medicinal Chemistry of the German Pharmaceutical Society (Deutsche Pharmazeutische Gesellschaft; DPhG), and supported by a local organizing committee from the Ludwigs‐Maximilians‐University Munich headed by Daniel Merk, the meeting brought together approximately 225 participants from 20 countries. The outstanding program of the four‐day conference included 40 lectures by leading scientists from industry and academia as well as early career investigators. Moreover, 100 posters were presented in two highly interactive poster sessions.

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A Yeast‐Based Assay for Inhibitors of l‐Lactate Transport Utilizing Fluorescent Biosensors

Tiedjens,

Menzel,

Stahnke

et al. 2024

ChemMedChem

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Inhibitors of ʟ‐lactate transport are in development as a novel mode of action in antitumor therapy and malaria. Previously, we used radiolabeled ʟ‐lactate to assay transport via the human monocarboxylate transporter 1, MCT1, and the structurally unrelated malaria parasite’s transporter, PfFNT. We encountered a sensitivity limit at IC50 around 100 nM possibly resulting from the required high cell number per sample. Here, we describe a sensitive background‐free high‐throughput assay in yeast based on fluorescent iLACCO biosensors. We used iLACCO for co‐expression and fusions with the transporter protein. Uptake of ʟ‐lactate produced strong intensiometric fluorescent responses that could be monitored in cell suspensions using a fluorometer and in individual cells by fluorescence microscopy. The signal decreased dose‐dependently in the presence of specific MCT1 and PfFNT inhibitors. Re‐evaluation of 36 PfFNT inhibitors yielded IC50 values below 100 nM now matching previous data on Ki compound affinity to isolated transporter protein.

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The Plasmodium Lactate/H ⁺ Transporter PfFNT Is Essential and Druggable In Vivo

Cited by 6 publications

References 35 publications

Emerging Drug Targets for Antimalarial Drug Discovery: Validation and Insights into Molecular Mechanisms of Function

Emerging Drug Targets for Antimalarial Drug Discovery: Validation and Insights into Molecular Mechanisms of Function

We are MedChem: The Frontiers in Medicinal Chemistry 2024

A Yeast‐Based Assay for Inhibitors of l‐Lactate Transport Utilizing Fluorescent Biosensors

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The Plasmodium Lactate/H + Transporter PfFNT Is Essential and Druggable In Vivo

Cited by 6 publications

References 35 publications

Emerging Drug Targets for Antimalarial Drug Discovery: Validation and Insights into Molecular Mechanisms of Function

Emerging Drug Targets for Antimalarial Drug Discovery: Validation and Insights into Molecular Mechanisms of Function

We are MedChem: The Frontiers in Medicinal Chemistry 2024

A Yeast‐Based Assay for Inhibitors of l‐Lactate Transport Utilizing Fluorescent Biosensors

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Product

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The Plasmodium Lactate/H ⁺ Transporter PfFNT Is Essential and Druggable In Vivo