Presentation Title

Developing chemical inhibitors to investigate the function of falcilysin, an essential mallarial protease

Faculty Mentor

Jeremy Mallari

Start Date

18-11-2017 2:15 PM

End Date

18-11-2017 3:15 PM

Location

BSC-Ursa Minor 99

Session

Poster 3

Type of Presentation

Poster

Subject Area

biological_agricultural_sciences

Abstract

Of the 5 species of malaria that infect humans, Plasmodium falciparum causes the most severe clinical symptoms. Malaria kills approximately 600,000 people annually, mostly African children. 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 4-bromobenzenesulfonyl at the N1 position and 4-phenylbenzoyl at the N4 position. These results are evidence that at the N4 position, relatively large, aromatic substituents contribute to a more effective inhibitor than alkyls do. Intermediates with different benzoyl moieties at the N4 position are in progress to find the most potent inhibitor. These inhibitors will further the study of FLN’s biological roles.

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Nov 18th, 2:15 PM Nov 18th, 3:15 PM

Developing chemical inhibitors to investigate the function of falcilysin, an essential mallarial protease

BSC-Ursa Minor 99

Of the 5 species of malaria that infect humans, Plasmodium falciparum causes the most severe clinical symptoms. Malaria kills approximately 600,000 people annually, mostly African children. 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 4-bromobenzenesulfonyl at the N1 position and 4-phenylbenzoyl at the N4 position. These results are evidence that at the N4 position, relatively large, aromatic substituents contribute to a more effective inhibitor than alkyls do. Intermediates with different benzoyl moieties at the N4 position are in progress to find the most potent inhibitor. These inhibitors will further the study of FLN’s biological roles.