Pharmaceutical Sciences Faculty Publications
Identification of Inhibitors of Trypanosoma brucei Hexokinases
Document Type
Web Publication
Publication Date
2011
PubMed ID
21961120
Abstract
The unicellular eukaryote Trypanosoma brucei (T. brucei) is the causative agent of human African trypanosomiasis (HAT), a disease that annually infects ~500,000 people in sub-Saharan Africa resulting in 50,000 – 70,000 deaths per year. Without treatment, HAT is fatal. Unfortunately, current treatments are limited in availability, have toxic side effects, are difficult to administer and are not well characterized in terms of their mechanism of action. Thus, the lack of affordable, safe, and effective therapies for those with African trypanosomiasis makes the identification of molecular target-specific chemotypes a priority in our effort to understand the mechanisms involved with parasite growth and viability, as well as for future therapeutic development. The probe identified from this effort, ML205, is a stable, small molecule possessing submicromolar activity (IC50 = 0.98 μM) against a defined T. brucei hexokinase 1 (rTbHK1) target. The probe was not toxic to mammalian cells (IMR-90 cells, EC50 > 25 μM) and mechanistic studies revealed that the probe operates with mixed inhibition with respect to ATP.
Keywords
Human African trypanosomiasis (HAT), Trypanosoma brucei, inhibitors, parasites
Recommended Citation
Sharlow, Elizabeth; Golden, Jennifer E.; Dodson, Heidi; Morris, Meredith; Hesser, Marcia; Lyda, Todd; Leimgruber, Stephanie; Schroeder, Chad E.; Flaherty, Daniel P.; Weiner, Warren S.; Simpson, Denise S.; Lazo, John S.; Aubé, Jeffrey; and Morris, James C., "Identification of Inhibitors of Trypanosoma brucei Hexokinases" (2011). Pharmaceutical Sciences Faculty Publications. 159.
https://digitalcommons.cedarville.edu/pharmaceutical_sciences_publications/159
Comments
In Probe Reports from the NIH Molecular Libraries Program. Bethesda, MD: National Center for Biotechnology Information, 2011.