Author Galina Lepesheva says this information provides the first up-close look at the busy enzyme and shows how one compound in particular prevents it from conducting business as usual. "It is our hope that the results of our work might be helpful for the development of an effective treatment", said Lepesheva.
Lepesheva and her team have set their sights on the trypanosomatidae family of parasites, which causes a trio of horrifying diseases: Human African Trypanosomiasis is transferred by the biting tsetse fly in sub-Saharan Africa. Its victims suffer only flulike symptoms in the first phase of infection, but it often is not diagnosed till after the parasite has entered the central nervous system, causing mental deterioration, mood swings, coma and death. Chagas disease is passed on by the reduviid, or "kissing bug," named for its tendency to bite victims around the lips, in South and Central America. The parasite is the world's leading cause of heart disease. Leishmaniasis, a disease transferred by the biting female sandfly, is prevalent in four continents and comes in four varieties, all of which either disfigure or kill its hosts.
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. 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," Lepesheva said. The researchers found: one of them 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.
MEDICA.de; Source: American Society for Biochemistry and Molecular Biology