Targeting Sleeping Sickness
Using the world's most powerful X-ray laser, researchers from the Deutsches Elektronen-Synchrotron DESY and their colleagues have identified a potential Achilles' heel in the pathogen causing sleeping sickness. The detailed structural analysis of an enzyme of the pathogen now provides the blueprint for a potential drug. This was the first time that a new biological structure was analysed using a free-electron laser.
According to WHO estimates, more than 500,000 people in sub-Saharan Africa are affected by sleeping sickness and over 60 million live with the threat. The disease, called also human African trypanosomiasis (HAT), is caused by the Trypanosoma brucei parasite, which is transmitted by the tsetse fly. The sleeping sickness derives its name from the typical coma state the patient exhibits in the end phase due to severe deterioration of the central nervous system. Without medical treatment, the disease is usually lethal. Since the currently used drugs are not sufficiently reliable and the parasite increasingly develops resistance against them, the development of new active agents is of great importance.
The enzyme investigated by the researchers goes by the name of cathepsin B and has been previously known as a point of attack for drugs. However, since it occurs not only in the parasite, but also in the human body, medication must target only the pathogen's version of the enzyme, without affecting the human enzyme. To decode the three-dimensional structure of cathepsin B, the research team subjected small crystals from this biomolecule to intensive X-ray radiation from the Linac Coherent Light Source (LCLS) at the SLAC National Accelerator Laboratory in California, USA. The enzyme crystals under investigation were about one thousandth of a millimetre (one micrometre) thick and on average ten micrometres long. Crystals scatter X-rays in a characteristic manner, so that the resulting diffraction images allowed the researchers to calculate the position of the individual atoms within the crystal and thus within the enzyme. To determine the structure of cathepsin B, they needed to produce hundreds of thousands of diffraction images and subsequently assemble them, with each image providing only one part of the structure.
In doing so, they have identified distinct differences between pathogenic and human cathepsin B. Precisely these differences can be used as point of attack for a new, tailored active agent, which targets the pathogenic enzyme and thereby kills the pathogen. Now, the next step would be the production and testing of such an active agent. Yet a new form of medication is still a long way off, the scientists point out. To allow for more of this kind of basic investigation of biomolecules, the building of an even better X-ray laser facility is well under way: the European X-ray free electron laser (European XFEL) is currently being built in Hamburg, with the DESY being its chief shareholder.