New Hope For Sleeping Sickness Drug
November 30, 2012

X-ray Laser May Be Key To Fighting Tsetse Fly Sleeping Sickness

Connie K. Ho for — Your Universe Online

Scientists from the Helmholtz Association of German Research Centers and the Department of Energy´s (DOE) SLAC National Accelerator Laboratory recently revealed that X-rays could provide information on a novel biological structure that could possibly be developed into a sleeping sickness drug.

The findings were discovered with the help of a free-electron laser that is considered the most powerful in the world. Sleeping disease affects over 60 million people in sub-Saharan Africa with a bite of the tsetse fly, and the researchers found a molecular plug that could selectively block an important enzyme of parasite Trypanosoma brucei to make it inactive then kill the parasite.

"This is the first new biological structure solved with a free-electron laser," commented Henry Chapman, a researcher with the Center for Free-Electron Laser Science in Hamburg, Germany, in a prepared statement.

With the help of the laser from the Linac Coherent Light Source (LCLS) at the U.S. National Accelerator Laboratory Lab, the researchers were able to study the small crystals of the parasite´s enzyme cathepsin B and determined that blocking the enzyme would have a negative impact. The researchers set bright X-ray flashes at the small cathepsin B crystals, scattering the X-rays and showing the structure of the enzyme. The X-ray lasers like LCLS can produce detailed diffraction images and the scientific light sources are based off of effective particle accelerators where lectors are accelerated at extremely high speeds.

"The enzyme had emerged as a promising drug target in earlier trials,” noted Lars Redecke, one of the study´s authors who served as a team leader of the research group, in the statement. "The knockdown of this essential enzyme in the parasite did cure the infection in mice."

In the study, the researchers tracked thousands of diffraction images that were later pieced together. The enzymes were frozen in the natural configuration and the researchers were able to see that there were different peptide bindings site in the human form versus the in the parasite.

“With the peptide still in place we could peer below a previously impenetrable part of the cathepsin B structure,” explained Christian Betzel, a professor at the University of Hamburg, in the statement. "This way, nature provided us with a blueprint of what an artificial inhibitor for the parasite's enzyme could look like."

The scientists were able to target the structural differences between the enzyme of the human and the enzyme of the parasite with the analysis.

“This should in principle allow for designing a molecule that selectively blocks the parasite's enzyme while leaving the patient's intact,” remarked one of the study´s first authors Karol Nass, a doctoral student at the Hamburg School for Structure and Dynamics in Infection (SDI), in the statement.

The results are particularly important, as the sleeping disease has had a wide impact on the sub-Saharan population. It is found in 36 sub-Saharan countries, mostly affecting people living in remote rural areas. Treatment with the infection is usually fatal, with the parasites moving towards the central nervous system. Even with control measures, millions of people are still at risk for the disease.

"This is really a landmark in structural biology, and a significant step toward developing a new drug," remarked Redecke in the statement.

Moving forward, the team is focusing on crystallizing proteins that are related to other parasites and viruses. These could also be observed at LCLS. The researchers believe that this field of research will continue to expand.

"Our study will encourage others to use free-electron lasers to obtain new structural information of biologically relevant molecules," concluded Redecke in the statement.

The findings were recently published in Science Express.