Critical interdependencies between Plasmodium nutrient flux and drugs

Henshall, Isabelle G.; Spielmann, Tobias

doi:10.1016/j.pt.2023.08.008

Trends in Parasitology

2023

DOI: 10.1016/j.pt.2023.08.008

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Critical interdependencies between Plasmodium nutrient flux and drugs

Isabelle G. Henshall,

Tobias Spielmann

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2024

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Cited by 2 publications

References 78 publications

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Plasmodium falciparum ring-stage plasticity and drug resistance

Platon,

Ménard

2024

Trends in Parasitology

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Plasmodium falciparum ring-stage plasticity and drug resistance

Platon,

Ménard

2024

Trends in Parasitology

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Addressing the Intracellular Vestibule of the Plasmodial Lactate Transporter PfFNT by p-Substituted Inhibitors Amplifies In Vitro Activity

Nerlich,

Tiedjens,

Hertel

et al. 2024

J. Med. Chem.

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Inhibition of the lactate transporter PfFNT is a valid novel mode of action against malaria parasites. Current pyridinesubstituted pentafluoro-3-hydroxy-pent-2-en-1-ones act as substrate analogs with submicromolar EC 50 in vitro, and >99.7% activity in mice. The recently solved structure of a PfFNT-inhibitor complex visualized the binding mode. Here, we extended the inhibitor layout by series of amine-and anilide-linked pyridine p-substituents to generate additional interactions in the cytoplasmic vestibule. Virtual docking indicated hydrogen bonding to Tyr31 and Ser102. Fluorescence cross-correlation spectroscopy yielded respectively enhanced target affinity. Strikingly, the in vitro activity increased by 1 order of magnitude to 14.8 nM at negligible cytotoxicity. While pamine substitutions were rapidly metabolized, the more stable pacetanilide cleared 99.7% of parasites at 4 × 50 mg kg −1 in a mouse malaria model. Future stabilization of the p-substitution against metabolism may translate the gain in in vitro potency to the in vivo situation.

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Critical interdependencies between Plasmodium nutrient flux and drugs

Cited by 2 publications

References 78 publications

Plasmodium falciparum ring-stage plasticity and drug resistance

Plasmodium falciparum ring-stage plasticity and drug resistance

Addressing the Intracellular Vestibule of the Plasmodial Lactate Transporter PfFNT by p-Substituted Inhibitors Amplifies In Vitro Activity

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