The silicon trypanosome: a system biology approach to improve drug target selection in African trypanosome

LEROUX, ALEJANDRO E.; KRAUTH-SIEGEL, R. LUISE

Heidelberg

Congreso; 12th Drug Design & Development Seminar; 2011

Deutsche Gesellschaft für Parasitologie

Trypanosoma brucei is the etiologic agent of human African trypanosomiasis, one of the most important neglected diseases in sub-Saharan Africa. Although African sleeping sickness is fatal if untreated, the current available drugs are far from satisfactory due to severe adverse effects as well as problems with efficacy, administration, and compliance. The Silicon Trypanosome project aims at the creation of a comprehensive, experiment-based, multi-scale mathematical model of trypanosome physiology. As the glycolytic pathway in bloodstream T. brucei has already been successfully modelled, this project will take the next step by expanding the established model by including the pentose phosphate pathway (main source of reducing power) and the unique trypanothione-based redox metabolism of the parasite which is already the target of several of the current chemotherapy drugs. As part of this project, we will study the kinetics of the different redox enzymes under pseudo-physiological conditions. To accomplish this task we have defined a buffer composition that will mimic as much as possible the intracellular milieu of bloodstream T. brucei. Moreover, the cellular concentration and where appropriate the redox state of the different enzymes will be determined to establish the flux through a certain point in the pathway. These experimental data will form the bases for a detailed computational model of parasite biology, that should allow to predict how the organism reacts to a wide range of perturbations. We expect that, in the long run, the quantitative modelling enabled by the Silicon Trypanosome will play a key role in selecting molecular targets for new anti-parasite drugs.