After many years of study, a team of researchers is now releasing data that it hopes will lead to new drug therapies that will kill the family of parasites that causes a deadly trio of insect-borne diseases and has afflicted inhabitants of underdeveloped and developing nations for centuries.
In an article to be published in January 16 issue of the Journal of Biological Chemistry, Vanderbilt University scientist Galina Lepesheva and her team are reporting their successful attempt at determining the structure of an enzyme essential to the survival of the protozoan parasites that cause sleeping sickness, Chagas disease and leishmaniasis. They say this new information provides the first up-close look at the busy enzyme and, perhaps more importantly, shows how one compound in particular prevents it from conducting business as usual.
"With human migrations, HIV co-infections and the broadening of the host reservoirs due to climate changes, sleeping sickness and other diseases caused by these protozoan pathogens are now spreading around the world, including within the United States and Europe," said Lepesheva, a research associate professor at the Vanderbilt's department of biochemistry. "It is our hope that the results of our work might be helpful for the development of an effective treatment for such protozoan infections, some of which still remain incurable."
Lepesheva and her team have set their sights on the trypanosomatidae family of parasites, which causes a trio of horrifying diseases:
Screening for trypanosomal diseases is challenging, because they most often affect people in remote locations with few or no medical resources, and existing treatments lack specificity and can cause severe side effects.
Lepesheva and her team sought to damage the single-celled parasite's cellular membrane, knowing that if they could weaken that barrier, the regulation of the intercellular environment would be disrupted, and the parasite would die.
"It has been known for some time that T. brucei, the parasite that causes sleeping sickness, consumes cholesterol in its human host's blood to shore up the cellular membrane, and researchers presumed there was no getting around that," Lepesheva said. "But we suspected the parasite, like plants and animals, still might need to make its own sterols for growth and development -- functional sterols -- that could be targeted and inhibited."
The team chose to attack the parasite's enzyme known as 14DM, which is short for sterol 14α-demethylase. They picked 14DM because it has a counterpart in fungi, which cause athlete's foot and ringworm, and such fungal infections are commonly treated with drugs that prevent 14DM from making ergosterol, a sterol required for membrane synthesis.
"We tested hundreds of compounds as potential 14DM inhibitors. One of them, VNI, was one of the best in terms of killing the parasites that cause sleeping sickness, Chagas and Leishmaniasis," she said.
The team named the inhibitor VNI, short for Vienna Novartis Inhibitor, because it originally was synthesized at the Novartis Research Institute in Vienna. It binds with the worker enzyme, a lot like a piece fits snugly into a jigsaw puzzle, and blocks the enzyme's ability to make the critical sterol.
Lepesheva said having a clear picture of the structure of the enzyme and how VNI fits into it explains why VNI is effective, and it opens the door to structure-based new drug design.
Lepesheva, the lead author on study, works in the laboratory of professor Michael Waterman, chairman of the department of biochemistry at Vanderbilt. They collaborated with researchers at Vanderbilt, Nashville's Meharry Medical College, the University of Toronto, the Universite Libre de Bruxelles in Belgium, Northwestern University and Texas Tech University. The work was supported by funding from the American Heart Association and the National Institutes of Health.
Materials provided by American Society for Biochemistry and Molecular Biology. Note: Content may be edited for style and length.
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