New rationally designed modulators of enzyme import into the glycosome in Trypanosoma parasites

Glycosomes are organelles characteristic of some unicellular organisms, including the Trypanosoma parasite. Glycosomes are genetically related to peroxisomes found in higher organisms, but in parasites they play a much more important role. It is enough to mention glycolysis, which is the only source of energy in the form of adenosine triphosphate (ATP) for T. brucei, the parasite that causes African coma. Glycolysis is a less important source of energy for the Chagas disease-causing T. cruzi, but this microorganism carries out other important biochemical processes in glycosomes, such as the synthesis of sterol, pyrimidines, and reduction of trypanothio.

Glycosomes are unable to produce their own enzymes for these essential processes, so these proteins must be transported from the cytosol. They are directed to this organelle with the participation of proteins called peroxins (PEX). Of these, PEX14 and PEX5 are the most important. Their combination is believed to allow the enzyme to be transferred across the membrane of the glycosome. Hence, blocking the formation of such a complex can inhibit enzymatic transport and consequently lead to severe negative metabolic effects. It has been proven that the inhibition of the activity of individual glycolytic enzymes by small-molecule organic compounds may result in the death of the parasite cell.

Diminishing the function of all enzymes at once by blocking their import into the target organelle should have at least as severe consequences.

This project aims to obtain new chemical compounds, small-molecule inhibitors that will prevent the PEX14-PEX5 proteins from joining, block the import of enzymatic proteins into the glycosome and, as a result, cause the death of the parasite's cell. So far, only one class of such compounds has been obtained, which in addition had inadequate pharmacological properties, and thus potentially low activity in biological systems. The main goal of the project is therefore to create new classes of inhibitors with at least equal PEX14 binding and protozoal activity, but with better properties such as solubility and pharmacokinetic profile. For this purpose, research methods such as computer-aided design of ligands based on the protein structure, organic synthesis as well as biophysical and cellular assays will be used. The conclusions drawn from the research will not only provide a better understanding of the biochemical processes taking place in glycosomes, but may also lay the groundwork for the design of new, alternative therapeutic strategies for deadly tropical diseases caused by parasites of genus trypanosomes.