Selective Inhibitors of Plasmepsin II of Plasmodium falciparum on the Basis of Pepstatin

A number of new inhibitors of plasmepsin II (PlmII) Plasmodium falciparum, which was one of the key factors of survival of malarial parasite, was synthesized. The inhibitors were analogues of pepstatin with different substitutions for the alanine residue. Effects of the inhibitors on human PlmII and cathepsin D were studied. Inhibition of PlmII by the substrate was found. This discovery required modification of the Henderson method for determination of inhibition constants. Two synthesized inhibitors were shown to exhibit a pronounced selectivity to PlmII (K-i = 5.5 and 5 nM) in comparison with that of cathepsin D (K-i = 230 and 3000 nM, respectively).