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Beating Trypanosomes

A bug that carries Chagas disease.
Above: Triatoma sanguisuga, a bug that carries Chagas disease. Photo by Jim Gathany / Arizona Department of Health Services

Late last week, a group of researchers from the University of Ibadan in Nigeria published a paper (Parasitology Res., DOI: 10.1007/s00436-011-2516-z) on several herbal extracts that can kill the parasites that cause sleeping sickness. Unfortunately, important projects like that are few and far between.

I’m almost done writing an article about drugs in development to treat sleeping sickness and Chagas disease, a pair of illnesses caused by a class of protozoans called trypanosomes. My story explains that the current treatments take several weeks, and the drugs have a wide variety of side effects ranging from rashes and headaches to neurological damage and death.

One of my sources seemed to be overly confident that better treatments for these diseases are just around the corner based on the early performance of several compounds that are in clinical trials.  I’m not convinced. Not long ago, a compound codenamed DB-289 entered Phase III trials for sleeping sickness. Everything seemed to be going well. And then, suddenly, the trial was halted due to safety concerns.

A handful of promising new drugs are making their way through clinical trials, and a few academic labs are looking for new compounds that can kill trypanosomes. Here is a roundup of some of those substances:

Phthalazines
A recent improvement upon the series of phthalazines developed by Manuel Sanchez-Moreno, Fernando Gomez-Contreras, and their colleagues in Granada, Spain.
Very early stage, Chagas disease

DDD85646
Identified by an academic library screening project, this compound inhibits N-myristoyltransferase in the trypanosomes that cause sleeping sickness.
Preclinical, sleeping sickness

SCYX-7158
An oxaborole similar to the ones developed by Anacor pharmaceuticals, a company that is testing boron-based drugs for a wide variety of antimicrobial applications.
Late stage preclinical, sleeping sickness.

K777
An inhibitor of the protease Cruzain, developed at UCSF, it may enter human trials within a year.
Late stage preclinical, Chagas disease

Posaconazole
Already on the market as an antifungal drug, it kills T. cruzi in vitro tests.
Preclinical, Chagas

Fexinidazole
Developed by Hoechst and shelved, DNDi resurrected this broad-spectrum agent.
Phase I, sleeping sickness.

E-1224
Eisai developed this azole prodrug as an antifungal agent. It is formulated as a monolysine salt.
Phase II, Chagas disease

DB-289
Proved effective, but trials were halted after participants showed signs of liver toxicity and renal insufficiency.
Phase III, sleeping sickness

Sleeping Sickness Drug Targets
Pteridine Reductase, N-myristoyltransferase, Trypanosome alternative oxidase, BILBO1, glycosylphosphatidylinositol membrane anchors

Chagas Disease Drug Targets
Lanosterol 14α-Demethylase, Superoxide Dismutase, cytochrome P450 sterol 14-demethylase, Cruzain

Here are some great sources of further information.

All about diagnostics for Human African Trypanosomiasis, or Sleeping Sickness, by the Foundation for Innovative New Diagnostics. Link
The rapid strip test for Chagas disease, developed by PATH. PDF Link
Here is an absolutely fantastic video of Professor Jim Mckerrow talking about Chagas disease. Link
And here’s a video of Mckerrow talking about sleeping sickness. Link
The eflornithine story. Link

Here’s my short list of what seems to be needed to beat these diseases.
A noninvasive test that can tell whether someone has stage 2 sleeping sickness, meaning that the parasites have crossed the blood-brain barrier.
Rapid tests that can tell whether Chagas disease or sleeping sickness have been cured, are getting better, or are getting worse.
Rapid tests for Chagas and sleeping sickness that use antibodies as recognition elements.
More safe, oral treatments for both diseases.

Do you have something to add? Please tell me about it. I’ll be updating this post every so often.
Aaron Rowe is this year’s C&EN Intern.

1 Comment

  • Aug 1st 201117:08
    by See Arr Oh

    Aaron: How about Bill Roush’s T. cruzei program (in collaboration with UCSF, compound WRR-483)
    See: http://www.plosntds.org/article/info%3Adoi%2F10.1371%2Fjournal.pntd.0000825

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