Date of Award
8-2026
Document Type
Thesis
Degree Name
Master of Science (MS)
College/School
College of Science and Mathematics
Department/Program
Chemistry and Biochemistry
Thesis Sponsor/Dissertation Chair/Project Chair
Nina Goodey
Committee Member
Eli Lee
Committee Member
Kathleen Frey
Abstract
Lymphatic filariasis, commonly known as elephantiasis, afflicts >657 million individuals across 59 countries and remains a neglected tropical disease with limited therapeutic options. Wuchereria bancrofti (Wb), the parasitic worm responsible for over 90% of filariasis cases replicate in the lymphatic system of affected individuals through transmission by mosquito vectors. Current therapeutics involving mass drug administration do not target the adult worm, but are designed to reduce microfilariae in the blood, hence, the need for therapeutics that targets both the adult worm and microfilariae. Due to the critical role dihydrofolate reductase (DHFR) plays in folate metabolism and DNA synthesis, we hypothesize that it is an important target in developing therapeutics that targets the adult worm and its microfilarae. In this study, potential antifolate inhibitors of WbDHFR were investigated to advance therapeutics for lymphatic filariasis. These compounds were aimed at targeting DHFR from Wuchereria bancrofti while sparing the human DHFR, to prevent parallel or off-target inhibition. The rate-limiting step of the reaction involving WbDHFR was also examined to better understand the enzyme’s kinetics using kinetic isotope effects involving protium (H2O) and deuterium (D2O) in a single and multiple turnover experiment, and solvent viscosity effect with glycerol at varying concentrations. A virtual screening of antifolate compounds led to the identification of propargyl-linked antifolate compounds such as PLA XCO1-172, 1195, 1187, 1162, 1038, 1278, 1181 and 1162. These compounds were tested in an inhibition assay, and IC50 and Ki values were determined using IC50 plots. The inhibitory profile and kinetic behaviour of WbDHFR can be better understood based on these experimental findings, and potentially advance efforts to create targeted antifolate treatments that may target both adult worms and microfilariae.
File Format
Recommended Citation
Otu-Aboagye, David, "Antifolate Inhibition and Kinetic Probing of Wucereria bancrofti Dihydrofolate Reductase: Developing Therapeutics for Lymphatic Filariasis" (2026). Theses, Dissertations and Culminating Projects. 1740.
https://digitalcommons.montclair.edu/etd/1740