The researchers at JGU have demonstrated how a specific inhibitory substance docks on to and deactivates a vital protein of the parasite that is involved in African sleeping sickness.

‘The findings of the study would lead to the development of treatments that could potentially cure a dramatic number of people and cattle in sub-Saharan regions affected by the sleeping sickness.’

Currently, only a handful of drugs to treat sleeping sickness, which is fatal if left untreated, are available and these treatments are often accompanied by severe side effects and even fatalities in up to 10 percent of patients. Although new drugs are currently being developed, the approach of Hellmich's group goes one step further: "Our inhibitor opens up the future prospect of being able to design inhibitors on a fundamental level and could thus possibly also be used in the treatment of infection with other, related pathogenic parasites, such as Leishmania," Annika Wagner, lead author of the study recently published in Angewandte Chemie International Edition, pointed out. 




Inhibitor induces dimerization of essential parasite protein
The principle is based on the fact that a small, selective inhibitor binds to the enzyme tryparedoxin. This protein is essential for the parasite, protecting it from oxidative damage, but is not present in humans, making it a viable drug target. To their surprise, the team of researchers discovered that when the inhibitor binds to the protein, two of the resulting inhibitor-protein complexes then combine to form a stable dimer. When this occurs, the usually monomeric protein ceases to function.
"We were astonished and initially thought it was a chance effect due to experimental conditions," said Hellmich. The investigation was then extended, and it was verified in a large-scale study using various methods that the dimerization effect could be reproduced. In addition to the Mainz research teams of Professor Ute Hellmich and Professor Till Opatz, researchers from the universities of Frankfurt, Würzburg, Heidelberg, and the European Molecular Biology Laboratory (EMBL) in Grenoble were involved.
Highly interdisciplinary research proves successful
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By precisely demonstrating the mechanism by which the parasite protein is chemically inhibited and dimerized by the small molecule, the interdisciplinary research partnership has staked out the fundamentals underlying such a new concept. "It was crucial that we didn't stop at our original goal of merely determining the crystal structure of the protein-inhibitor complex," said Hellmich. "Instead, we took a second look at the result and then discussed it with experts from different fields. Research only progresses when we work together."
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Source-Eurekalert