Degree Type


Date of Award


Degree Name

Master of Science


Biochemistry, Biophysics and Molecular Biology



First Advisor

Scott W. Nelson


Malaria is caused by the parasite Plasmodium falciparum, and is amongst the world’s most deadly infectious diseases for which there is no vaccine. Malaria is currently controlled through drug therapy, but the formation of resistance is common and new drugs that target novel parasite functions are urgently needed. P. falciparum contains an essential non-photosynthetic organelle called the apicoplast. The apicoplast harbors its own DNA and a single DNA polymerase (apPOL) is targeted to the apicoplast to carry-out genomic replication and repair. apPOL has no direct ortholog with mammalian polymerases, making it an appealing drug target for the treatment and/or prevention of malaria. The Medicines for Malaria Venture (MMV) selected 400 structurally diverse compounds that resulted from very large-scale screening campaigns performed by St. Jude Children's Research Hospital, Novartis, and GSK. These compounds are able to kill P. falciparum in cultured red blood cells and are non-toxic to cultured human cells, but their molecular targets are unknown. We previously screened the Malaria Box for apPOL inhibitors and identified a single compound (MMV666123) that completely inhibits apPOL at a concentration of 10 µM. This thesis describes the kinetic characterization of that compound, along with 36 additional structural derivatives that were generated by our collaborators in an effort to improve inhibitor potency. In addition, to guide the synthesis of additional derivatives, we determined the x-ray crystal structure of one of the derivatives bound to apPOL. The compound binds at a previously unidentified allosteric pocket that sits adjacent to the polymerase active site. We propose that the binding of the derivative to the allosteric site prevents the polymerase from adopting the closed, active conformation of the enzyme. The allosteric site is present in other A-family polymerases, but the identity of the residues lining the pocket differ, suggesting the site could be targeted with high specificity.

Copyright Owner

Supreet Kaur



File Format


File Size

48 pages

Included in

Biochemistry Commons