Lipoic Acid Metabolism as a Potential Chemotherapeutic Target Against Plasmodium falciparum and Staphylococcus aureus

Yan, Sun; Wakasuqui, Felipe; Du, Xiaochen; Groves, Matthew R.; Wrenger, Carsten

doi:10.3389/fchem.2021.742175

Cited by 3 publications

(3 citation statements)

References 53 publications

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“…Thus, these organisms represent a unique opportunity for the development of selective LPL inhibitors in order to block LA-dependent central metabolism pathways and, thereby, growth. [13] Despite this intriguing opportunity and the urgent need for novel anti-infectives, the development of such inhibitors has not been significantly exploited. One example is the redox-inactive small molecule mimic of LA, 8-bromo octanoic acid (BrO), which is transferred via LPL to substrate proteins, but cannot further support enzymatic catalysis.…”

Section: Introductionmentioning

confidence: 99%

A Chemical Proteomic Strategy Reveals Inhibitors of Lipoate Salvage in Bacteria and Parasites

et al. 2023

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The development of novel anti-infectives requires unprecedented strategies targeting pathways which are solely present in pathogens but absent in humans. Following this principle, we developed inhibitors of lipoic acid (LA) salvage, a crucial pathway for the survival of LA auxotrophic bacteria and parasites but non-essential in human cells. An LA-based probe was selectively transferred onto substrate proteins via lipoate protein ligase (LPL) in intact cells, and their binding sites were determined by mass spectrometry. Probe labeling served as a proxy of LPL activity, enabling in situ screenings for cell-permeable LPL inhibitors. Profiling a focused compound library revealed two substrate analogs (LAMe and C3) as inhibitors, which were further validated by binding studies and co-crystallography. Importantly, LAMe exhibited low toxicity in human cells and achieved killing of Plasmodium falciparum in erythrocytes with an EC 50 value of 15 μM, making it the most effective LPL inhibitor reported to date.

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Section: Introductionmentioning

confidence: 99%

A Chemical Proteomic Strategy Reveals Inhibitors of Lipoate Salvage in Bacteria and Parasites

et al. 2023

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“…In addition to their role in PTMs, LA proved its essential role in redox regulation. Since LipL1 and LipL2 inhibitors are used as anti-cancer drugs, the reviewers recommended further studies investigating the efficacy of these inhibitors against Plasmodium in vitro and in vivo [66] .…”

Section: (B) Protein Lipidation Enzymesmentioning

confidence: 99%

Recent advances in identification of potential drug targets and development of novel drugs in parasitic diseases. Part IV. Plasmodium spp.

Abaza

2022

Parasitologists United Journal

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In the last two decades, transporters attracted much attention in identification of potential drug targets against intracellular protozoa. Several membrane molecules exhibit essential roles in trafficking pathways for nutrients, essential enzymes and virulence factors. In this context, P. falciparum possesses a complex of genomic plasticity-encoding transporters with high potentiality for aneuploidy, and gene expression modulation in response to drug exposure. Therefore, it is able to undergo gene mutations in enzymes controlling drug uptake, and evade host immune response by antigenic variations as well. The genetic mechanism of antimalarial drug resistance arises early with monotherapy using fast-acting drugs or a single targeting drug. Accordingly, combined therapy acting on multiple targets would decrease the emergence of drug resistance. Evolutionary technology on genetic approach enabled researchers to identify and propose novel Plasmodium drug targets. The main objective of this part is to review potential drug targets for apicomplexans and discuss recent approaches in identifying Plasmodium targets, as well as advances in the design and development of novel antimalarial drugs.

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“…Daher stellen diese Orga-nismen eine einzigartige Gelegenheit für die Entwicklung selektiver LPL-Inhibitoren dar, um LA-abhängige zentrale Stoffwechselwege zu blockieren und somit das Wachstum zu hemmen. [13] Trotz dieser interessanten Möglichkeit und dem dringenden Bedarf an neuen Antiinfektiva wurde die Entwicklung solcher Inhibitoren bisher nicht wesentlich genutzt. Ein Beispiel dafür ist das redox-inaktive Derivat von LA, 8-Bromoctansäure (BrO), das über LPL auf Substratproteine übertragen wird, aber die enzymatische Katalyse nicht weiter unterstützen kann.…”

Section: Introductionunclassified

Eine chemisch‐proteomische Strategie identifiziert Inhibitoren der Lipoat‐Wiederverwertung in Bakterien und Parasiten

et al. 2023

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Die Entwicklung neuer Antiinfektiva erfordert innovative Strategien zur gezielten Ausnutzung von Stoffwechselwegen in Krankheitserregern, die in menschlichen Zellen abwesend sind. Basierend auf diesem Prinzip haben wir Hemmstoffe der Liponsäure (LA) Wiederverwertung entwickelt, einem entscheidenden Stoffwechselweg für das Überleben von LA‐auxotrophen Bakterien und Parasiten, der jedoch in menschlichen Zellen nicht essentiell ist. Eine auf LA basierende Sonde wurde selektiv über die Lipoatproteinligase (LPL) auf Substratproteine in intakten Zellen übertragen, und ihre Bindungsstellen wurden mittels Massenspektrometrie bestimmt. Die Intensität der Markierung mit der Sonde diente als Maß für die Aktivität von LPL und ermöglichte intrazelluläre Selektion für zellpermeable LPL‐Hemmer. Das Testen einer vorselektierten Substanzbibliothek ergab zwei Substratanaloga (LAMe und C3) als Hemmstoffe, die durch Bindungsstudien und Co‐Kristallographie weiter validiert wurden. Bemerkenswert ist, dass LAMe eine geringe Toxizität in menschlichen Zellen aufwies und eine Abtötung von Plasmodium falciparum in Erythrozyten mit einem EC50‐Wert von 15 μM erreichte, was diesen Stoff zum bisher wirksamsten LPL‐Hemmer macht, der jeher berichtet wurde.

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Lipoic Acid Metabolism as a Potential Chemotherapeutic Target Against Plasmodium falciparum and Staphylococcus aureus

Cited by 3 publications

References 53 publications

A Chemical Proteomic Strategy Reveals Inhibitors of Lipoate Salvage in Bacteria and Parasites

A Chemical Proteomic Strategy Reveals Inhibitors of Lipoate Salvage in Bacteria and Parasites

Recent advances in identification of potential drug targets and development of novel drugs in parasitic diseases. Part IV. Plasmodium spp.

Eine chemisch‐proteomische Strategie identifiziert Inhibitoren der Lipoat‐Wiederverwertung in Bakterien und Parasiten

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