East African Sleeping Sickness
These blood and tissue protozoa cause human sleeping sickness in Africa (Trypanosoma brucei brucei; Trypanosoma brucei gambiense) and veterinary diseases in most domesticated animals (T. b. brucei and related species). These species inhabit 10 million square kilometers of sub-saharan Africa and cause significant human hardship and economic loss. As a result of local civil strife and deplorable health care conditions in Africa both the human and veterinary diseases are spreading. Drug development, with one important exception, has remained at the same level for the past half century. Despite efforts of the World Health Organization and philanthropic organizations, African trypanosomiasis remains an orphan disease for which few drug leads and limited drug development funding exists. Our laboratory developed the one new drug effective against human sleeping sickness, DFMO or eflornithine. Used clinically for >25 years, DFMO has saved thousands of lives, but is considered expensive at $500 per patient and difficult to administer. Research with sleeping sickness focused on the metabolism of polyamines, low molecular weight compounds needed by cells for growth and division. DFMO blocks ornithine decarboxylase, the initial enzyme of polyamine synthesis. In collaboration with DNDi, Scynexis and Anacor we have identified a series of oxoborols that are effective in curing trypanosome model infections. These compounds will enter phase I clinical trials in early 2010.
Student projects include: in vitro testing of new compounds for antitrypanosomal in 24 well plates; study of highly active compounds in an in vivo mouse model assay; and the examination of the possible mechanism(s) of action of active compounds within polyamine metabolism in trypanosomes.