Pharmaceutical Sciences Faculty Publications

Title

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

Comments

In Probe Reports from the NIH Molecular Libraries Program. Bethesda, MD: National Center for Biotechnology Information, 2011.