Developing Chemical Inhibitors to Investigate the Function of Falcilysin, a Malarial Protease

Event Center BC

Plasmodium falciparum is one of five species of malaria parasite that infects people, and causes over 500,000 deaths annually. After entering the human host, P. falciparum infects red blood cells (RBCs) where the parasite grows and replicates for approximately 48 hours before lysing the host cells and starting a new round of infection. The parasite relies on a range of proteases in order to infect and grow within RBCs, though the functions of some of these proteases are not well characterized. Our research is investigating the function of an essential but poorly understood parasite protease called falcilysin (FLN). We are working towards the development of specific and potent chemical inhibitors of FLN. These inhibitors will provide much-needed tools to study FLN loss-of-function phenotypes in cultured parasites. Our inhibitors are based on a piperazine ring backbone with a hydroxamic acid moiety. Our current inhibitor panel is investigating how different substitution patterns on the piperazine ring influence inhibitor activity against FLN. Here we present the synthesis of these compounds as well their inhibitory potency against recombinant FLN protein.