Title

Effect of 3-methyleneoxindole and Its Derivatives on Viability of Trypanosoma Brucei

Document Type

Grant Proposal

Date Accepted

Spring 2008

Project Description/Abstract

Trypanosoma brucei, the etiologic agent of African sleeping sickness, is responsible for illness and death in humans and their domesticates in the tsetse belt of Africa. New drugs are beginning to result from recent biochemical discoveries. The indole acetic acid derivatives 3-methyleneoxindole (MOI) and glutathionyl-MOI (GSMOI) affect thiol enzymes in many cells and were recently tested on procyclic stage trypanosomes where they were shown to cause dose-dependent killing. These compounds kill trypanosomes in culture at micromolar concentrations, as measured by loss of motility and altered membrane permeability. They also inhibit the activity of an essential enzyme, trypanothione reductase (TR), making them potential lead compounds against this parasite drug target. The goal of this project is enrichment of this enzyme from crude trypanosome cell homogenates or by cloning parasite DNA to improve the kinetic analysis (Km, Vmax and Ki) essential to understanding the mechanism of action of these compounds.

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