Countering Sleeping Sickness

People with sleeping sickness—also known as African trypanosomiasis—could one day take a new class of medication to cure it, at least in the disease’s initial stage.

Sleeping sickness causes some 30,000 deaths annually when biting tsetse flies infect humans with the Trypanosoma brucei protozoan. Existing treatments for the disease can have deadly side effects or require sophisticated health care infrastructure that is rare in sub-Saharan Africa, where the disease is most prevalent.

Now, an international team of 26 researchers led by Paul G. Wyatt, a chemist at the University of Dundee’s Drug Discovery Unit, in Scotland, report a promising class of drug leads against the sleeping sickness parasite. The compounds are pyrazole sulfonamide derivatives that can be taken as a pill and that have cured mice of early infections (Nature 2010, 464, 728).

The compounds inhibit an important enzyme called N-myristoyltransferase in T. brucei. This enzyme decorates certain proteins with the fatty molecule myristic acid, permitting the proteins to associate with the cell membrane, where they play crucial roles in cell signaling.

“It’s truly exciting to see some selective compounds for N-myristoyltransferase,” which was initially evaluated as a target for antifungal drugs, comments Katherine Brown, a biochemist at Imperial College London. This new study furthers the possibility of using the enzyme as a target for other protozoan diseases such as leishmania and malaria, she adds.

The drug leads, particularly one called DDD85646, can cure mice of stage 1 infections—that is, before the parasite infects the central nervous system. However, DDD85646 can’t chase the pathogen once it crosses the blood-brain barrier, causing stage 2 of the disease, when those infected fall into a coma and eventually die.

The team of researchers is now tweaking DDD85646 so that it can cross the blood-brain barrier and is having some successes, Wyatt says.

“We also hope that the current drug leads will have potential as a veterinary drug,” he says. “Sleeping sickness also causes billions of dollars of loss in wealth and income from animal deaths in sub-Saharan Africa. Sleeping sickness is a big economic problem, alongside its role as a human disease.”

Current treatments for sleeping sickness include an arsenic-based drug called melarsoprol, which kills 5% of patients taking the medicine, and eflornithine, which involves multiple two-hour intravenous infusions over the course of two weeks and requires heavy equipment that is hard to set up in rural Africa, Wyatt says.