Developing Chemical Inhibitors for the Malarial Protease, Falcilysin

RM 215

Malaria kills approximately 500,000 people annually, mostly African children. Of the 5 species of malaria that infect humans, Plasmodium falciparum causes the most severe clinical symptoms. Falcilysin (FLN) is an essential metalloprotease found within the apicoplast, food vacuole and cytosol of P. falciparum. Although it was discovered because of its ability to degrade hemoglobin-derived peptides in the food vacuole, its functions in other parts of the cell are unknown. Previous attempts to genetically knockout FLN have failed, indicating that FLN is essential for survival of the parasite. Our goal is to use previously developed synthetic routes to create potent and selective chemical inhibitors that can be used to perform a chemical knockout of FLN in live parasites. This knockout will allow us to study FLN-null phenotypes and perform loss of function studies. Our current inhibitors are piperazine-based hydroxamic acids with different aryl sulfonyl groups at the N1 position and a variety of substituents at the N4 position. Hydroxamic acids are known to coordinate with the catalytic zinc at the active sites of the metalloprotease, leading to an increase in potency. Ongoing work to test these inhibitors against recombinant falcilysin and live parasites indicates that the most effective substituents are substituted benzenesulfonyl rings at the N1 and N4 position. Currently, I am most interested in determining the effects on inhibition of size, electron withdrawal and steric strain at the N4 position.