Molecular Curanderos

Carlos Faerman, Cornell University
Richard Gillilan, Cornell Theory Center

Chagas' disease, or American trypanosomiasis, afflicts more than 18 million people in Central and South America. Control of this disease is a top priority at the World Health Organization's Division of Control of Tropical Diseases, superceded only by Malaria and Schistosomiasis. In southern South America, health workers hope to stop the spread of the disease by the turn of the century through improved living conditions and blood bank screening. However, the parasite will continue infecting an additional one million people each year until its spread is halted. And one third of those infected will experience chronic health problems.

Molecular modeler Carlos Faerman works with biochemist Andrew Karplus and chemist Bruce Ganem (all at Cornell University) on a research team that is searching for a molecular cure for Chagas' disease. The team seeks to chemically control the disease by stripping the parasitic organism of its defenses. Working with Cornell Theory Center visualization specialist Richard Gillilan, Faerman is using virtual reality techniques running on the world's largest IBM SP system to explore the molecular structures of the disease. They are examining the disease's defense system and studying ways to design a new drug molecule that will shut it down.

Chagas' disease is caused by the parasite Trypanosoma cruzi (T. cruzi), which enters the body through mucus membranes and passes through the circulatory system to invade individual tissue cells. Approximately one third of the humans infected sustain permanent and incurable damage. The disease is lethal to children under the age of two. The most common result of infections is chronic heart disease; however the incurable lesions also cause digestive and neurological disorders in nearly 10 percent of those chronically affected. Currently 45,000 victims die each year, many of them children.

T. cruzi must maintain high levels of the chemical, trypanothione, within the cell it is attacking to protect itself from naturally toxic by-products of normal metabolism. The level of trypanothione within the cell is regulated by the enzyme, trypanothione reductase (TR). A drug that inhibits this enzyme could kill the parasite. But would it also interfere with the biology of the host cells?

The Ganem/Karplus team believe they can develop a treatment that will be safe for human cells. Research by others has shown that glutathione and glutathione reductase (GR), a very similar pair of molecules occurring in humans might be in jeopardy. The structures of both the TR and GR enzyme molecules have been solved using X-ray crystallography methods. Both molecules are dimers, consisting of two similar parts, each with its own active site. However, when the molecules were simulated and viewed in 3D, researchers observed that the two molecules have opposite electrostatic charges, suggesting that a molecule designed to inhibit the activity of one enzyme should not affect the activity of the other.

Using CTC's Visual Insight Zone virtual reality environment, Faerman and Gillilan are studying a long tunnel through the center of the TR enzyme that connects the active sites of its two similar halves. Any molecule passing through such a tunnel will undoubtedly interact with bits and pieces of the enzyme molecule along the sides of the walls as it passes through the enzyme on its way to and/or from the active site.

The researchers are examining the behavior of a number of compounds that show potential as drugs to treat Chagas' disease in this virtual space to see if and how the compounds bind and lock the active sites and to study the roles played by such important structural features as the tunnels.

Molecules at Work
Top Priority
Chagas' Disease