Starving Out Malaria Parasites

New class of selective inhibitors paralyze essential plasmodium enzymes

The most dangerous variant of the malaria parasite, Plasmodium falciparum, infects up to 600 million people every year. The search for new effective therapies is thus an urgent area of research. An international team headed by François Diederich has now found a new point of attack: using a novel class of inhibitors, the researchers aim to block certain plasmodium enzymes known as plasmepsins, “starving out” the malaria parasite.

Plasmepsins belong to the family of aspartic protease enzymes. They dismantle human hemoglobin to deliver the amino acids that plasmodia need in order to grow. In developing a new inhibitor, it is important to ensure that it blocks all of the plasmodium plasmepsins while remaining inactive toward human aspartic proteases.

The team of researchers from the Swiss Federal Institute of Technology (ETH) in Zurich, the University of Victoria (Canada), Washington University, St. Louis (USA), and Actelion Pharmaceuticals in Allschwil (Switzerland) started with the previously determined spatial structure of one of the plasmepsins, plasmepsin II. This enzyme has a sort of pocket, formed by the opening of a peptide loop, which seemed to be a suitable point of attack for an inhibitor. On the basis of computer simulations, the researchers successfully developed a family of molecules that fit well into this cavity. The central structural element of these molecules is a bicyclic diamine framework: a six-membered ring of carbon atoms in which two opposite carbon atoms are additionally bridged by the nitrogen of the amino group. A second amino group is bound to a neighboring carbon atom. Like a pincer, the diamine framework clamps onto the catalytic dyad (the two catalytically active aspartate groups) of the plasmepsin. An additional side group fits into a second, adjacent pocket (S1/S3-cavity) of the enzyme.

Enzymatic assays pointed the way to the most effective molecules. It was demonstrated that these did not only block plasmepsin II, for which they were specifically tailored: plasmodium plasmepsins I and IV were both even more strongly inhibited. These enzymes clearly have a very similar structure. In contrast, human aspartyl proteases seem to have a completely different spatial structure because they are not affected at all. In cell cultures of plasmodium-infected red blood cells, the new inhibitors were able to inhibit the growth of the parasites. “We are now trying to further improve the activity of the inhibitors,” says Diederich, “with the goal of developing a new class of antimalaria agents.”