Plasmepsin II is a key enzyme in the life cycle of the @entity3964 parasites responsible for @entity311 , a disease that afflicts more than 300 million individuals annually. Since plasmepsin II inhibition leads to starvation of the parasite, it has been acknowledged as an important target for the development of new antimalarials. In this paper, we identify and characterize high-affinity inhibitors of plasmepsin II based upon the @entity69190 scaffold. The best compound, @entity69568 , inhibits plasmepsin II with a K(i) of 70 nM and a 22-fold selectivity with respect to the highly homologous @entity1 enzyme @entity10815 . @entity69568 binds to plasmepsin II in a process favored both enthalpically and entropically. At 25 degrees C, the binding enthalpy (DeltaH) is -4.4 kcal/mol and the entropic contribution (-TDeltaS) to the Gibbs energy is -5.56 kcal/mol. Structural stability measurements of plasmepsin II were also utilized to characterize inhibitor binding. High-sensitivity differential scanning calorimetry experiments performed in the absence of inhibitors indicate that, at pH 4.0, plasmepsin II undergoes thermal denaturation at 63.3 degrees C. The structural stability of the enzyme increases with inhibitor concentration in a manner for which the binding energetics of the inhibitor can quantitatively account. The effectiveness of the best compounds in killing the @entity311 parasite was validated by performing @entity137 assays in red blood cells infected with @entity3964 . EC50s ranging between 6 and 10 microM (3-6 microg/mL) were obtained. These experiments demonstrate the viability of the @entity69190 scaffold in the design of powerful and selective plasmepsin inhibitors.

Identification and characterization of XXXX -based inhibitors of plasmepsin II, an antimalarial target.

@entity1 :: ('9606', 'Species') :: ['human'] @entity10815 :: ('1509', 'Gene') :: ['cathepsin D'] @entity137 :: ('MESH:D064420', 'Disease') :: ['cytotoxicity'] @entity69568 :: ('MESH:C435823', 'Chemical') :: ['KNI-727'] @entity3964 :: ('5833', 'Species') :: ['Plasmodium falciparum', 'Plasmodium'] @entity311 :: ('MESH:D008288', 'Disease') :: ['malaria'] @entity69190 :: ('MESH:C034940', 'Chemical') :: ['allophenylnorstatine']
@entity69190 :: (MESH:C034940,Chemical) :: ['allophenylnorstatine']
