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• W1537278345 abstract "Malaria remains a major public health problem and the increasing number of resistantstrains underscores the need for new drugs with new modes of action (MOAs).It was the aim of the present thesis to characterize a novel antimalarial lead compoundwith respect to MOA and in vitro properties.The lead compound, ACT-AM, inhibited in vitro proliferation of all tested P. falciparumstrains, irrespective of their drug resistance properties, with IC50 values in the low singledigitnanomolar range. ACT-AM was further shown to equally and rapidly affect allasexual blood stages of the parasite. The novel molecule is therefore comparable to themost efficacious registered antimalarial drugs in terms of in vitro activity.To investigate the MOA of ACT-AM, a chemical derivative of the compound able toform covalent bonds upon UV activation was utilized. This advantageous UV-dependentsystem was adapted and implemented for P. falciparum- notably for the use in intact cellsand proved to be appropriate for various biochemical methods including pull-downexperiments, fluorescent imaging and Far Western blotting. Pull-down experimentsrevealed numerous target candidates, three of which were shown to interact with ACTAMin vitro, namely MDR (multidrug resistance protein), ENT4 (equilibrative nucleosidetransporter 4) and CRT (chloroquine resistance transporter). These proteins couldrepresent actual targets or might confer resistance to the compound.Microarray and hematin interaction studies suggested that ACT-AM has an MOA distinctfrom that of several registered antimalarials, a factor that bodes well for possiblecombination therapies.The promising in vitro activity of the compound and the indication of a novel MOAemphasize the potential of ACT-AM or analogues of the same chemical class astherapeutic agents for the treatment of malaria." @default.
• W1537278345 created "2016-06-24" @default.
• W1537278345 creator A5046383425 @default.
• W1537278345 date "2011-01-01" @default.
• W1537278345 modified "2023-09-24" @default.
• W1537278345 title "A novel antimalarial lead compound: in vitro properties and mode of action studies" @default.
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