Abstract
The liver stage of Plasmodium's life cycle is the first, obligatory step in malaria infection. Decreasing the hepatic burden of Plasmodium infection decreases the severity of disease and constitutes a promising strategy for malaria prophylaxis. The efficacy of the gamma-secretase and signal peptide peptidase inhibitor LY411,575 in targeting Plasmodium liver stages was evaluated both in human hepatoma cell lines and in mouse primary hepatocytes. LY411,575 was found to prevent Plasmodium's normal development in the liver, with an IC50 of approximately 80 nM, without affecting hepatocyte invasion by the parasite. In vivo results with a rodent model of malaria showed that LY411,575 decreases the parasite load in the liver and increases by 55% the resistance of mice to cerebral malaria, one of the most severe malaria-associated syndromes. Our data show that LY411,575 does not exert its effect via the Notch signaling pathway suggesting that it may interfere with Plasmodium development through an inhibition of the parasite's signal peptide peptidase. We therefore propose that selective signal peptide peptidase inhibitors could be potentially used for preventive treatment of malaria in humans.
Highlights
Malaria is a devastating parasitic disease accounting for 1 to 2 million deaths per year, mostly among children in Sub-Saharan Africa, Asia, Central and South America
LY411,575 reduces the load of P. berghei ANKA in hepatic cells in a dose-dependent manner
In order to measure the influence of LY411,575 on P. berghei development monolayers of human hepatoma Huh7 cells cultured in 24-well tissue culture plates, were treated with concentrations of the inhibitor ranging from 100 to 750 nM
Summary
Malaria is a devastating parasitic disease accounting for 1 to 2 million deaths per year, mostly among children in Sub-Saharan Africa, Asia, Central and South America. During the last two decades, the incidence of malaria has been increasing, largely due to an emergence of parasite variants resistant to the two most widely used drugs, chloroquine and sulphadoxine/pyrimethamine. This fact, taken together with the largely unsuccessful attempts for antimalarial vaccination, makes the development of new drugs against this disease critically important [1]. The liver stage of the disease is clinically silent while all pathological manifestations develop during the blood stage [7,8]. All currently used antimalarial agents, with the exception of primaquine, target blood stage parasites. Drugs against liver stage malaria would block the development of the parasites and prevent pathology. It is crucial to develop novel agents against this stage of infection
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