STRUCTURE AND INHIBITION OF PLASMEPSIN-II, A HEMOGLOBIN-DEGRADING ENZYME FROM PLASMODIUM-FALCIPARUM

Plasmodium falciparum is the major causative agent of malaria, a disea se of worldwide importance, Resistance to current drugs such as chloro quine and mefloquine is spreading at an alarming rate, and our antimal arial armamentarium is almost depleted, The malarial parasite encodes two homologous aspartic proteases, plasmepsins I and II, which are ess ential components of its hemoglobin-degradation pathway and are novel targets for antimalarial drug development, We have determined the crys tal structure of recombinant plasmepsin II complexed with pepstatin A. This represents the first reported crystal structure of a protein fro m P. falciparum. The crystals contain molecules in two different confo rmations, revealing a remarkable degree of interdomain flexibility of the enzyme. The structure was used to design a series of selective low molecular weight compounds that inhibit both plasmepsin II and the gr owth of P. falciparum in culture.