Presentation Title

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

Faculty Mentor

Jeremy Mallari

Start Date

17-11-2018 8:30 AM

End Date

17-11-2018 10:30 AM

Location

CREVELING 108

Session

POSTER 1

Type of Presentation

Poster

Subject Area

biological_agricultural_sciences

Abstract

The protozoan parasite Plasmodium falciparum causes the most severe form of human malaria, a disease that imposes a massive burden on human health around the world. Falcilysin (FLN) is a metalloprotease expressed by the parasite, and is essential for its development within human erythrocytes. Our laboratory is working to develop selective small molecule inhibitors against FLN; this will provide chemical tools enabling us to modulate FLN activity in live parasites and to better understand the biological roles of this enzyme. We recently reported the development of a series of FLN inhibitors based on a piperazine-derived hydroxamic acid scaffold. Many of these compounds displayed potent activity against both the metalloprotease and against cultured parasites, suggesting that parasite killing was mediated by FLN blockade. Despite this correlation, we also identified a subset of inhibitors with anti-malarial activity that were inactive against FLN, suggesting that some compounds may act at alternative cellular targets. To better understand these discrepancies, we are synthesizing a series of chemical probes incorporating a photocrosslinkable diazirine group and an alkyne that functions as a click chemistry handle. These probes will allow us to directly identify the target(s) of each inhibitor, and will facilitate the development of selective inhibitors against FLN and other parasite metalloproteases.

Summary of research results to be presented

Research results include the IC-50 values of previously developed and tested small molecule inhibitors. The results of previously developed inhibitors will be in a format showing how we had an imperfect correlation between Falcilysin inhibition and the killing of the parasite. Based on the imperfect correlation I will present the photocrosslinkable click chemistry probes which will help us to better understand the discrepancy.

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Nov 17th, 8:30 AM Nov 17th, 10:30 AM

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

CREVELING 108

The protozoan parasite Plasmodium falciparum causes the most severe form of human malaria, a disease that imposes a massive burden on human health around the world. Falcilysin (FLN) is a metalloprotease expressed by the parasite, and is essential for its development within human erythrocytes. Our laboratory is working to develop selective small molecule inhibitors against FLN; this will provide chemical tools enabling us to modulate FLN activity in live parasites and to better understand the biological roles of this enzyme. We recently reported the development of a series of FLN inhibitors based on a piperazine-derived hydroxamic acid scaffold. Many of these compounds displayed potent activity against both the metalloprotease and against cultured parasites, suggesting that parasite killing was mediated by FLN blockade. Despite this correlation, we also identified a subset of inhibitors with anti-malarial activity that were inactive against FLN, suggesting that some compounds may act at alternative cellular targets. To better understand these discrepancies, we are synthesizing a series of chemical probes incorporating a photocrosslinkable diazirine group and an alkyne that functions as a click chemistry handle. These probes will allow us to directly identify the target(s) of each inhibitor, and will facilitate the development of selective inhibitors against FLN and other parasite metalloproteases.