1. Antiplasmodial activity and mechanism of action of RSM-932A, a promising synergistic inhibitor of Plasmodium falciparum choline kinase.
- Author
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Zimmerman T, Moneriz C, Diez A, Bautista JM, Gómez Del Pulgar T, Cebrián A, and Lacal JC
- Subjects
- Adenosine Triphosphate chemistry, Adenosine Triphosphate metabolism, Chloroquine pharmacology, Choline chemistry, Choline metabolism, Choline Kinase chemistry, Choline Kinase metabolism, Dose-Response Relationship, Drug, Drug Synergism, Enzyme Inhibitors pharmacology, Erythrocytes drug effects, Erythrocytes parasitology, Escherichia coli genetics, Humans, Kinetics, Parasitic Sensitivity Tests, Phosphorylation drug effects, Plasmodium falciparum enzymology, Plasmodium falciparum growth & development, Protozoan Proteins chemistry, Protozoan Proteins metabolism, Recombinant Proteins chemistry, Recombinant Proteins metabolism, Trophozoites drug effects, Trophozoites enzymology, Trophozoites growth & development, Aniline Compounds pharmacology, Antimalarials pharmacology, Antineoplastic Agents pharmacology, Butanes pharmacology, Choline Kinase antagonists & inhibitors, Plasmodium falciparum drug effects, Protozoan Proteins antagonists & inhibitors, Pyridinium Compounds pharmacology, Quinolinium Compounds pharmacology
- 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.
- Published
- 2013
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