Development of Click Chemistry Probes to Investigate the Function of Falcilysin, an Essential Malarial Protease

RM 215

The protozoan parasite Plasmodium falciparum causes approximately 500,000 fatal cases of malaria a year. FLN is an essential protease expressed by the parasite. Our goal is to better understand the biological role of FLN using selective piperazine-based hydroxamic acid inhibitors which will regulate the levels of FLN activity. Our lab recently developed the first known inhibitors of FLN. We tested these inhibitors against FLN and live parasites. Results show a correlation between the inhibition of FLN and the killing of the parasite. However, we found that some inhibitors are parasiticidal but show no activity toward FLN suggesting that these may be targeting other proteins in the cell. To better understand this, we are developing a new generation of inhibitors that can be photocrosslinked to these target proteins. The inhibitors will contain the necessary functional groups to allow us to isolate and identify the target proteins in the cell for each compound. The inhibitors will contain a diazirine group and an alkyne. The diazirine will allow for the inhibitor to covalently bond to the target protein upon exposure to ultraviolet light. Once the inhibitor is covalently bound we can use the alkyne to isolate proteins that our inhibitors targeted. These probes will allow for us to determine if our inhibitors are selectively targeting FLN or if they are targeting other proteins as well.