Parasitostatic effect of maslinic acid. I. Growth arrest of Plasmodium falciparum intraerythrocytic stages

Abstract

BackgroundNatural products have played an important role as leads for the development of new drugs against malaria. Recent studies have shown that maslinic acid (MA), a natural triterpene obtained from olive pomace, which displays multiple biological and antimicrobial activities, also exerts inhibitory effects on the development of some Apicomplexan, including Eimeria, Toxoplasma and Neospora. To ascertain if MA displays anti-malarial activity, the main objective of this study was to asses the effect of MA on Plasmodium falciparum-infected erythrocytes in vitro.MethodsSynchronized P. falciparum-infected erythrocyte cultures were incubated under different conditions with MA, and compared to chloroquine and atovaquone treated cultures. The effects on parasite growth were determined by monitoring the parasitaemia and the accumulation of the different infective stages visualized in thin blood smears.ResultsMA inhibits the growth of P. falciparum Dd2 and 3D7 strains in infected erythrocytes in, dose-dependent manner, leading to the accumulation of immature forms at IC50 concentrations, while higher doses produced non-viable parasite cells. MA-treated infected-erythrocyte cultures were compared to those treated with chloroquine or atovaquone, showing significant differences in the pattern of accumulation of parasitic stages. Transient MA treatment at different parasite stages showed that the compound targeted intra-erythrocytic processes from early-ring to schizont stage. These results indicate that MA has a parasitostatic effect, which does not inactivate permanently P. falciparum, as the removal of the compound allowed the infection to continueConclusionsMA displays anti-malarial activity at multiple intraerythrocytic stages of the parasite and, depending on the dose and incubation time, behaves as a plasmodial parasitostatic compound. This novel parasitostatic effect appears to be unrelated to previous mechanisms proposed for current anti-malarial drugs, and may be relevant to uncover new prospective plasmodial targets and opens novel possibilities of therapies associated to host immune response.

Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo

“…After centrifugation, the top and bottom phases were separated, vacuum dried, and independently analyzed by HPLC-PDA. Duplicates for each sample, condition, and time point were produced and analyzed (Table S2) (62). The number of animals was calculated using Statgraphics Centurion 16.1.18 software (Statpoint Technologies) to provide about 80% of statistical power with 95% confidence level, always following the 3Rs principles.…”

“…The in vivo study was carried out according to standard protocol following the 4-d suppressive test (61) implemented as previously described (20,62 For the present study with borrelidin analogs, to follow the 3Rs principles (63), we used a 99% value of suppression activity as previously obtained with borrelidin against P. yoelii yoelii 17XL (20) to calculate the minimal number of animals (n = 5) to detect a minimum suppression activity of 25% with 80% of statistical power (b = 0.2) and 95% confidence level (a = 0.05). BALB/ cAnNHsd mice were infected i.p.…”

Using a genome-scale metabolic network model to elucidate the mechanism of chloroquine action in Plasmodium falciparum

“…Because many studies suggest that PfDd2 is less sensitive to chloroquine than Pf3D7 (Moneriz et al., 2011), DNA synthesis might have been expected to be more inhibited in Pf3D7 than in PfDd2. In our simulations, however, a similar concentration of chloroquine resulted in greater DNA synthesis inhibition in PfDd2 (Fig.…”

A systematic review of pentacyclic triterpenes and their derivatives as chemotherapeutic agents against tropical parasitic diseases

“…Further analysis of the possible mechanism of action of MA suggested a multi routed mechanism involving the inhibition of a number of proteases necessary for the growth of the parasite. Other binding sites for MA, which include the Plasmodium phospholipase, were putatively proposed in an in silico analysis (Moneriz et al 2011c). This remarkable in vivo activity demonstrated by MA calls for similar investigation on other oleanane-type PT especially those with even lower in vitro IC 50 than MA such as epi-OA (11).…”