Abstract
We have investigated the mechanism of action of inhibition of the choline kinase of P. falciparum (p.f.-ChoK) by two inhibitors of the human ChoKα, MN58b and RSM-932A, which have previously been shown to be potent antitumoral agents. The efficacy of these inhibitors against p.f.-ChoK is investigated using enzymatic and in vitro assays. While MN58b may enter the choline/phosphocholine binding site, RSM-932A appears to have an altogether novel mechanism of inhibition and is synergistic with respect to both choline and ATP. A model of inhibition for RSM-932A in which this inhibitor traps p.f.-ChoK in a phosphorylated intermediate state blocking phosphate transfer to choline is presented. Importantly, MN58b and RSM-932A have in vitro inhibitory activity in the low nanomolar range and are equally effective against chloroquine-sensitive and chloroquine-resistant strains. RSM-932A and MN58b significantly reduced parasitemia and induced the accumulation of trophozoites and schizonts, blocking intraerythrocytic development and interfering with parasite egress or invasion, suggesting a delay of the parasite maturation stage. The present data provide two new potent structures for the development of antimalarial compounds and validate p.f.-ChoK as an accessible drug target against the parasite.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / chemistry
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Adenosine Triphosphate / metabolism
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Aniline Compounds / pharmacology*
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Antimalarials / pharmacology*
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Antineoplastic Agents / pharmacology*
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Butanes / pharmacology*
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Chloroquine / pharmacology
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Choline / chemistry
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Choline / metabolism
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Choline Kinase / antagonists & inhibitors*
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Choline Kinase / chemistry
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Choline Kinase / metabolism
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Dose-Response Relationship, Drug
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Drug Synergism
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Enzyme Inhibitors / pharmacology
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Erythrocytes / drug effects
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Erythrocytes / parasitology
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Escherichia coli / genetics
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Humans
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Kinetics
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Parasitic Sensitivity Tests
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Phosphorylation / drug effects
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Plasmodium falciparum / drug effects*
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Plasmodium falciparum / enzymology
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Plasmodium falciparum / growth & development
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Protozoan Proteins / antagonists & inhibitors*
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Protozoan Proteins / chemistry
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Protozoan Proteins / metabolism
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Pyridinium Compounds / pharmacology*
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Quinolinium Compounds / pharmacology*
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Recombinant Proteins / chemistry
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Recombinant Proteins / metabolism
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Trophozoites / drug effects
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Trophozoites / enzymology
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Trophozoites / growth & development
Substances
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1,4-(4-4'-Bis-((4-(dimethylamine)pyridinium-1-yl) methyl)diphenyl)butane dibromide
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Aniline Compounds
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Antimalarials
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Antineoplastic Agents
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Butanes
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Enzyme Inhibitors
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Protozoan Proteins
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Pyridinium Compounds
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Quinolinium Compounds
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RSM-932A
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Recombinant Proteins
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Chloroquine
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Adenosine Triphosphate
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Choline Kinase
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Choline