The prestigious journal Science has now published the results of a study examining new options for developing drugs against parasites of the Trypanosoma genus, which causes sleeping sickness and other diseases. Scientists from CEITEC at Masaryk University were among the members of an international team to discover new ways of targeted treatment.
The protozoa of the Trypanosoma genus cause a number of serious diseases affecting both animals and humans including sleeping sickness and Chagas disease, which affect millions of people worldwide. The existing drugs have a number of serious side effects and often fail to kill all the parasites, thereby creating a risk of relapse. This is why new and more effective drugs are needed.
“Our part of the research consisted of understanding the structures and the minor differences between the trypanosomal and human homologous proteins by using NMR spectroscopy,” says Konstantinos Tripsianes, the co-author of the study and leader of the Protein–DNA Interactions research group at CEITEC MU.
The scientists focused their search for new treatment options on glycosomes – small organelles typical for those protozoa that help transform glucose, or simple sugar, into energy. To do this, they need certain proteins called PEX.
As Tripsianes explains, “We focused on the interaction of two proteins, PEX5 and PEX14. The former is able to recognize the right enzymes and the latter helps transport them inside the glycosome. Our research primarily involved PEX14. We determined and compared its 3D structure in the parasites and in humans, as this process also takes place in human cells. We found that even though the structures of PEX14 proteins are very similar, there are differences at the PEX5 interaction surface that can help us target specifically the trypanosomal interaction.”
This allowed the researchers to create small molecules that block the PEX5-PEX14 interaction, thus blocking the glucose metabolism itself. The glucose then starts to accumulate inside the parasites’ cells and the parasites are eventually killed by metabolic failure. “Thanks to the differences between the proteins found in the parasites and those found in humans, the new compounds do not affect the glucose metabolism in human cells. PEX14 inhibitors could, therefore, become the foundation for developing new drugs against the trypanosomiasis group of diseases, such as sleeping sickness and Chagas disease,” adds Tripsianes.
