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The human malaria parasite  Plasmodium falciparum  is able to synthesize  de novo  pyridoxal 5-phosphate (PLP), a crucial cofactor, during erythrocytic schizogony. However, the parasite possesses additionally a pyridoxine/pyridoxal kinase (PdxK) to activate B6 vitamers salvaged from the host. We describe a strategy whereby synthetic pyridoxyl-amino acid adducts are channelled into the parasite. Trapped upon phosphorylation by the plasmodial PdxK, these compounds block PLP-dependent enzymes and thus impair the growth of  P. falciparum . The novel compound PT3, a cyclic pyridoxyl-tryptophan methyl ester, inhibited the proliferation of  Plasmodium  very efficiently (IC 50 -value of 14 µM) without harming human cells. The non-cyclic pyridoxyl-tryptophan methyl ester PT5 and the pyridoxyl-histidine methyl ester PHME were at least one order of magnitude less effective or completely ineffective in the case of the latter. Modeling  in silico  indicates that the phosphorylated forms of PT3 and PT5 fit well into the PLP-binding site of plasmodial ornithine decarboxylase ( Pf ODC), the key enzyme of polyamine synthesis, consistent with the ability to abolish ODC activity  in vitro . Furthermore, the antiplasmodial effect of PT3 is directly linked to the capability of  Plasmodium  to trap this pyridoxyl analog, as shown by an increased sensitivity of parasites overexpressing  Pf PdxK in their cytosol, as visualized by GFP fluorescence.

Poisoning Pyridoxal 5-Phosphate-Dependent Enzymes: A New Strategy to Target the Malaria Parasite Plasmodium falciparum