Identifizierung neuer Leitsubstanzen zur Hemmung der cAMP vermittelten Signalübermittlung bei Trypanosoma brucei

• Research unit: COST
• Project number: C98.0060

Key words (English)

Human sleeping sickness; chemotherapy; phosphodiesterase inhibitors

Research programs (English)

COST-Action B9 - Protozoal infections

Short description (English)

See abstract

Partners and International Organizations (English)

A, B, CZ, DK, F, D, NL, P, E, S, CH, GB

Abstract (English)

The overall aim of this project was to establish if the cAMP signalling pathways of Trypanosoma brucei might contain suitable targets for the development of new trypanocidal drugs. New and more effective drugs are desperately needed for the treatment of human sleeping sickness, a reemergent epidemic of catastrophic proportions in large parts of Sub-Saharan Africa. In view of the fact that phosphodiesterase inhibitors have proven very successful in clinical pharmacology, for treating human ailments ranging from allergy to impotency (Viagra® !), we have concentrated on the identification and characterization of the cyclic nucleotide specific phosphodiesterases of Trypanosoma brucei, the causative agent of human sleeping sickness. We have identified and partially characterized 4 different phosphodiesterase isoenzymes. One of them, the TbPDE2 enzyme family was demonstrated pharmacologically and genetically as being essential for cell proliferation. Two members of this family were biochemically characterized in detail and were expressed as recombinant proteins in the yeast S. cerevisiae and, subsequently through a collaboration with a pharmaceutical company, in insect cells. The recombinant enzyme was then used for a high-throughput screening of a proprietary compound library ( about 250'000 compounds), and a number of hits were retrieved. The detailed characterization of these compounds, and the hit-to-lead development are currently in progress. The goals set at the beginning of the project have been reached beyond our initial expectations, and the project has been instrumental in launching a new, industry-financed development program to explore phosphodiesterase inhibitors as potential anti-leishmanial and anti-malarial compounds.

References in databases (English)

Swiss Database: COST-DB of the State Secretariat for Education and Research Hallwylstrasse 4 CH-3003 Berne, Switzerland Tel. [phone] Swiss Project-Number: C98.0060