Crystallization and Study of Dihydrofolate Reductases (DHFR) in Wuchereria bancrofti and Brugia malayi.

Abstract

Lymphatic Filariasis, commonly regarded as Elephantiasis, is a vastly untreated parasitic disease primarily caused by the worms Wuchereria bancrofti and Brugia malayi which affects ~63 million people in 73 countries. Current drug treatments, such as diethylcarbamazine and ivermectin, are effective drug treatments when the host is initially infected; however, upon onset of limb swelling, these treatments fail to eradicate the parasites. Dihydrofolate Reductase (DHFR), a vital and ubiquitous enzyme that aids in DNA synthesis and folate metabolism, is a well‐established drug target and may result in a treatment option for many suffering from the disease. Selective inhibition of DHFR in both organisms may lead to progress in combating the disease and therefore aiding those who are infected. Currently, the lack of three‐dimensional understanding of both enzymes poses as an obstacle for selective inhibition. Crystallization and X‐Ray diffraction of these enzymes would elucidate their respective binding sites which will provide an understanding of how these enzymes function and thus, providing insight as to how to introduce inhibition. Once crystal structures of both enzymes are obtained with and without ligand bound, rational drug design can begin. Currently, both DHFR enzymes are being expressed and purified by Dr. Goodey's research lab and several inhibition studies have already been carried about; however, crystallization procedures have recently begun to ultimately provide a detailed model as to how the enzymes function within these organisms. In the future and as a result of this project, kinetic studies can then subsequently be carried out to test possible selective inhibitors.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.