Plasmodium falciparum Choline Kinase Inhibition Leads to a Major Decrease in Phosphatidylethanolamine Causing Parasite Death

This work was supported by Agencia Aragonesa para la Investigación y Desarrollo (ARAID), Ministerio de Economía y Competitividad (CTQ2013-44367-C2-2-P to R.H.-G.) and Diputación General de Aragón (DGA; B89 to R.H.-G.) and the EU Seventh Framework Programme (2007–2013) under BioStruct-X (grant agreement 283570 and BIOSTRUCTX 5186, to R.H.-G.). T.K.S. was supported by the Wellcome Trust grant 093228 and European Community’s Seventh Framework Programme under grant agreement No. 602773 (Project KINDRED).Malaria is a life-threatening disease caused by different species of the protozoan parasite Plasmodium, with P. falciparum being the deadliest. Increasing parasitic resistance to existing antimalarials makes the necessity of novel avenues to treat this disease an urgent priority. The enzymes responsible for the synthesis of phosphatidylcholine and phosphatidylethanolamine are attractive drug targets to treat malaria as their selective inhibition leads to an arrest of the parasite’s growth and cures malaria in a mouse model. We present here a detailed study that reveals a mode of action for two P. falciparum choline kinase inhibitors both in vitro and in vivo. The compounds present distinct binding modes to the choline/ethanolamine-binding site of P. falciparum choline kinase, reflecting different types of inhibition. Strikingly, these compounds primarily inhibit the ethanolamine kinase activity of the P. falciparum choline kinase, leading to a severe decrease in the phosphatidylethanolamine levels within P. falciparum, which explains the resulting growth phenotype and the parasites death. These studies provide an understanding of the mode of action, and act as a springboard for continued antimalarial development efforts selectively targeting P. falciparum choline kinase.Publisher PDFPeer reviewe

GRAIN BOUNDARY DIFFUSION OF Co AND Ni IN BICRYSTALLINE AND POLYCRYSTALLINE NiO

La diffusion intergranulaire de Co et de Ni a été étudiée dans des bicristaux de NiO de flexion symétrique d'axe et . Aucune diffusion préférentielle le long des joints n'a été mise en évidence. Il est vraisemblable que la diffusion intergranulaire des cations est au plus égal à 103D, et non de l'ordre de 105D comme il a été publié. En outre, il est peu probable que les impuretés soient entièrement responsables des divergences observées.Grain boundary diffusion of Co and Ni has been studied in and symmetrical tilt NiO bicrystals. No preferential intergranular diffusion has been detected. It is thought that cation diffusion along grain boundaries is less than 103D, where D is the lattice diffusion coefficient, and not of the order of 105D as published. Moreover, it is unlikely that impurities are entirely responsible for the discrepancies

CORRELATION BETWEEN MICROSTRUCTURE OF NiO GRAIN-BOUNDARIES AND INTERGRANULAR DIFFUSION

Une diffusion intergranulaire préférentielle de Ni et de Co a été signalée dans de l'oxyde de nickel polycristallin obtenu par oxydation thermique du nickel. Ces résultats ne sont pas confirmés sur du NiO obtenu par d'autres procédés. La structure des joints est sans doute responsable de la différence de comportement.An enhanced intergranular diffusion of Ni and Co was observed in polycrystalline NiO prepared by thermal oxidation of nickel. These results are not confirmed in nickel oxide prepared by other methods. The structure of the grain-boundaries is believed to be responsible for this different behaviour

Influence of strong transannular N → P interaction on acidity of cyclenphosphine sulfide

International audienceThe acid-base behavior of cyclenphosphine sulfide (cyclenPS) is appreciably different from that of cyclamphosphine sulfide (cyclamPS). The cyclenPS shows five acid functionalities compared to four for cyclamPS. The fifth acidic group in cyclenPS corresponds to the formation of a stable amidure in aqueous solution (pK(a5) = 12.3). This behavior is due to the strong transannular N → P interaction. The deprotonation sequences were established by 31P-NMR and confirmed by modelling of cyclenPS