Event Title

Developing Chemical Tools to Investigate Falcilysin, an Essential Malarial Metalloprotease

Presenter Information

Nikolay Maslov

Presentation Type

Oral Presentation

Major

Chemistry and Biochemistry

Category

Biological and Agricultural Sciences

Session Number

01

Location

RM 215

Faculty Mentor

Dr. Jeremy Mallari

Juror Names

Jeremy Dodsworth, Angela Horner, Dung Vu

Start Date

5-16-2019 1:40 PM

End Date

5-16-2019 2:00 PM

Abstract

The malarial parasite Plasmodium falciparum kills an estimated 445,000 people annually, with the most deaths occurring in African children. Previous studies show that falcilysin (FLN) is a metalloprotease essential to the parasite’s development in the human host, though its biological role is poorly understood. The parasite is notoriously resistant to genetic modification. In order to study FLN, we are developing chemical inhibitors to block FLN activity in live parasites in order to conduct loss-of-function studies. Previous data demonstrates that the binding pocket of interest in the metalloprotease is highly receptive to bulky non-polar substituents at the N4 position. In this study, we synthesized several inhibitors with various linkers to attach a phenyl to the N4 position. We then tested them against the metalloprotease and determine their inhibition potency. Collected data shows that a sulfonamide in combination with a lengthy akyl linker results in the most potent inhibitors to date. This information will aid in the development of chemical tools to determine the function of this protease and evaluate FLN as a therapeutic target against malaria.

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May 16th, 1:40 PM May 16th, 2:00 PM

Developing Chemical Tools to Investigate Falcilysin, an Essential Malarial Metalloprotease

RM 215

The malarial parasite Plasmodium falciparum kills an estimated 445,000 people annually, with the most deaths occurring in African children. Previous studies show that falcilysin (FLN) is a metalloprotease essential to the parasite’s development in the human host, though its biological role is poorly understood. The parasite is notoriously resistant to genetic modification. In order to study FLN, we are developing chemical inhibitors to block FLN activity in live parasites in order to conduct loss-of-function studies. Previous data demonstrates that the binding pocket of interest in the metalloprotease is highly receptive to bulky non-polar substituents at the N4 position. In this study, we synthesized several inhibitors with various linkers to attach a phenyl to the N4 position. We then tested them against the metalloprotease and determine their inhibition potency. Collected data shows that a sulfonamide in combination with a lengthy akyl linker results in the most potent inhibitors to date. This information will aid in the development of chemical tools to determine the function of this protease and evaluate FLN as a therapeutic target against malaria.