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Galina Lepesheva, Ph.D., and Michael Waterman, Ph.D., are studying the structure of an enzyme crucial to the parasite that causes African sleeping sickness. (photo by Joe Howell)

Study may lead to new drugs to combat sleeping sickness

BY: BILL SNYDER

2/05/2010 - Vanderbilt University researchers and their colleagues have determined the structure of an enzyme essential to the survival of Trypanosoma brucei, the protozoan parasite that causes African sleeping sickness.

The discovery could lead to new, more effective treatments for the often-fatal tropical disease, as well as for Chagas disease, prevalent in Central and South America, and leishmaniasis, which has reached epidemic proportions in parts of Africa, Brazil and Afghanistan.

All three diseases are caused by trypanosomatids, single-celled parasites transmitted by insect bites that are notoriously resistant to treatment and eradication, and which afflict millions of people.

Aided primarily by increased intercontinental travel, these diseases are spreading rapidly around the world, including the United States, said Galina Lepesheva, Ph.D., lead author of the report published Jan. 15 as a paper of the week and cover article in the Journal of Biological Chemistry.

“Our work may provide the basis for developing an effective treatment for such protozoan infections,” said Lepesheva, research associate professor of Biochemistry at Vanderbilt. “They are deadly. Chagas disease is still incurable.”

Currently, Lepesheva and her colleagues, including Jeffrey Johnston, Ph.D., professor of Chemistry and co-director of the Vanderbilt Chemical Synthesis Core, are designing specific inhibitors of the enzyme that could be used in combination with current drug regimens to kill Trypanosoma brucei more efficiently and with fewer side effects.

Lepesheva came to Vanderbilt in 2000 as a post-doctoral fellow from Minsk, Belarus, to work with Michael Waterman, Ph.D., chair of Biochemistry.

Both researchers are experts in a family of enzymes used throughout the animal kingdom to make sterols, lipid molecules essential for cell membrane function and integrity.

“Without the appropriate membrane structure the organisms can't reproduce and don't survive,” said Waterman, the paper's senior author.

Drugs used to treat fungal infections such as athlete's foot and ringworm work by a similar mechanism, by preventing sterol biosynthesis, and they also can kill Trypanosoma brucei.

But until the structure of the parasite's enzyme was solved, it was not known that these drugs bind to the enzyme like keys in a lock, or how researchers might design a better key.

Most drugs used to treat fungal infections are topical, applied to the skin.
Now it may be possible to develop safer, more effective oral medications, not only for protozoan infections, but for systemic fungal infections in people whose immunity is impaired by diseases like AIDS, Waterman said.

Co-authors of the paper include Fernando Villalta, Ph.D., and Minu Chaudhuri, Ph.D., trypanosomatid experts at Nashville's Meharry Medical College, as well as researchers at the University of Toronto, the Free University of Brussels, Northwestern University and Texas Tech University.

The study was supported by the National Institutes of Health and the American Heart Association.

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