Semester of Graduation
Spring 2026
Degree Type
Thesis
Degree Name
Master of Science in Integrative Biology
Department
Molecular and Cellular Biology
Committee Chair/First Advisor
Kojo Mensa-Wilmot
Second Advisor
Masafumi Yoshinaga
Third Advisor
Soon Goo Lee
Abstract
Human African trypanosomiasis (HAT) is an infectious disease caused by Trypanosoma brucei. Mostly prevalent in regions of sub-Saharan Africa, it is a deadly disease if it is left untreated. The existing drugs are suboptimal, and their administration sometimes requires the difficult task of clinical monitoring of patients in rural Africa. The only USFDA-approved drug, Fexinidazole, is associated with some patient non-compliance. This situation calls for renewed effort to find new leads for anti-HAT drug development. Quinolinimine analog NEU- 4438 is a lead compound that reduces trypanosome load 100-fold in a mouse model of HAT. It inhibits nuclear DNA synthesis, reduces maturation of the basal bodies, and inhibits transferrin endocytosis. We optimized hit compounds, structural analogs of NEU-4438, against T. brucei and found some hits in the screening funnel. In mode-of-action studies, it was found that advanced hits can inhibit nuclear DNA synthesis, reduce maturation of basal bodies, and inhibit transferrin endocytosis, like NEU-4438. Some selective hits also inhibited bovine serum albumin (BSA) endocytosis. These advanced hits also disrupt the steady state amount of TbRP2 protein, which is a transition zone fiber protein at the distal appendages of the basal body, where flagella begin. This finding led us to test whether these hits are responsible for reducing flagellar growth. The data suggested that these inhibit flagellum growth as well. We conducted a dose-ranging exploratory study to determine a safe and effective dosage for animal administration.