Pharmacological effect of MEK inhibitors on plasmodium falciparum

[摘要] Malaria continues to kill up to 3 million people each year, and parasite resistance to drugs is a pressing problem. Protein kinases are now prime targets for chemotherapy in a variety of diseases such as cancer and neurodegenerative diseases, and have been proposed as potential targets for antimalarial intervention. Our group is engaged in research aiming at characterising Plasmodium protein kinases at the biochemical and functional levels, with emphasis on homologues of enzymes that are known regulators of proliferation and differentiation in eukaryotic cells.The Mitogen Activated Protein Kinases (MAPKs) are quasi-ubiquitous in eukaryotes, where they play crucial roles in the regulation of cell proliferation and differentiation in response to extra-or intracellular stimuli. The MAPKs typically function in 3-component modules comprising the MAPK and upstream MAPKKs (MEKs) and MAPKKKs (MEKKs). Surprisingly, experimental and in silico analyses have demonstrated P. falciparum does not possess any MEK homologues, even though its kinome comprises two members of the MAP kinase family. Prior to the finding that the parasite does not possess MEKs, it had been shown in our laboratory that U0126, a MEK inhibitor, had parasitocidal activity in vitro. To confirm and extend these data, a panel of structurally distinct MEK inhibitors, most of which are not ATP competitors (and hence are likely to bemore selective than more classical PK inhibitors) was tested on cultured P. falciparum. It is striking that most of the MEK inhibitors kill P. falciparum with EC50s that compare very well with those against mammalian cells. The absence of MEK-encoding genes in the Plasmodium genome suggests that the target may be a host erythrocyte MEK. Consistent with this hypothesis, we detected an increase of MEK phosphorylation in infected red blood cells (RBCs) compared to uninfected RBCs, using a panel of antibodies directed against the activated, phosphorylated form of MEK1. In the presence of MEK inhibitors, the signal decreased in infected red blood cells. Furthermore, we show that U0126 does not act during invasion or within the first 24 hours of the asexual cycle, but during the trophozoite stage. Taken together, our data strongly suggest that infection with P. falciparum modulates the MAP kinase pathway in its host erythrocyte, and that the parasite relies on this pathway for its own survival.

[发布机构] University:University of Glasgow;Department:Institute of Infection Immunity and Inflammation

[关键词] Plasmodium falciparum, host MAP kinase