Title:Drug Development Against Sleeping Sickness: Old Wine in New Bottles?
Volume: 21
Issue: 15
Author(s): J. Stein, S. Mogk, C.N. Mudogo, B.P. Sommer, M. Scholze, A. Meiwes, M. Huber, A. Gray and M. Duszenko
Affiliation:
Keywords:
Apoptosis, autophagy, drug development, human african trypanosomiasis, sleeping sickness, Trypanosoma
brucei.
Abstract: Atoxyl, the first medicinal drug against human African trypanosomiasis (HAT), also known as sleeping
sickness, was applied more than 100 years ago. Ever since, the search for more effective, more specific and less toxic
drugs continued, leading to a set of compounds currently in use against this devastating disease. Unfortunately, none of
these medicines fulfill modern pharmaceutical requirements and may be considered as therapeutic ultima ratio due to
the many, often severe side effects. Starting with a historic overview on drug development against HAT, we present a
selection of trypanosome specific pathways and enzymes considered as highly potent druggable targets. In addition, we
describe cellular mechanisms the parasite uses for differentiation and cell density regulation and present our considerations
how interference with these steps, elementary for life cycle progression and infection, may lead to new aspects
of drug development. Finally we refer to our recent work about CNS infection that offers novel insights in how trypanosomes
hide in an immune privileged area to establish a chronic state of the disease, thereby considering new
ways for drug application. Depressingly, HAT specific drug development has failed over the last 30 years to produce
better suited medicine. However, unraveling of parasite-specific pathways and cellular behavior together with the ability
to produce high resolution structures of essential parasite proteins by X-ray crystallography, leads us to the optimistic
view that development of an ultimate drug to eradicate sleeping sickness from the globe might just be around the
corner.
