Abstract

Plasmodium falciparum, the primary causative agent of malaria in humans, is responsible for life-threatening infections and disease in many tropical regions of the world. In 2018, there were over 228 million cases and 405,000 deaths due to malaria infection, according to World Health Organization estimates. While there has been recent progress in decreasing mortality rates attributed to malaria, the emergence of widespread antimalarial drug resistance in recent decades has endangered such progress. Therefore, there is an urgent need for new antimalarial drugs with a novel mechanism of action.

Plasmodium kinases could serve as attractive drug targets due to their essential functions in all stages of the parasite’s life cycle. Plasmodium falciparum Aurora-related kinases (PfArks) have essential regulatory roles in all stages of the parasite’s asexual intraerythrocytic life cycle. As a result, it is hypothesized that PfArks are excellent potential molecular targets for novel antimalarial development.

The intent of this study was to identify potent and selective inhibitors of Plasmodium from an Aurora kinase-focused commercial inhibitor library of 3,000 compounds. An initial phenotypic screen was performed at a fixed inhibitor concentration of one micromolar to identify novel compounds with potency against the P. falciparum chloroquine-resistant Dd2 strain. From this library, we have identified multiple compounds with submicromolar antiplasmodial activity in asexual intraerythrocytic life cycle stages and adequate selectivity. Additionally, this project aimed further to characterize the cellular mechanism of action of hit compounds. Multiple compounds were found to exhibit inhibitory effects against early intraerythrocytic asexual life cycle stages as well as liver stages. At this time, one hit compound (DC-6275) was found to inhibit asexual intraerythrocytic as well as liver stage parasites in addition to PfArk1 amongst other Plasmodium protein kinases tested. Overall, we believe that these identified compounds have great potential to serve as scaffolds for future antimalarial drug development.

Thesis Completion

2020

Semester

Spring

Thesis Chair

Chakrabarti, Debopam

Degree

Bachelor of Science (B.S.)

College

College of Medicine

Department

Burnett School of Biomedical Sciences

Degree Program

Biomedical Sciences

Language

English

Access Status

Campus Access

Length of Campus-only Access

5 years

Release Date

5-1-2025

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