Oxopiperazine derivatives peptidomimetics as potential inhibitors of PEX14 and PEX5 protein interactions

Parasites of the genus Trypanosoma have a unique cell physiology as they carry out important glycolytic and peroxisomal processes in one organelle, the glycosome. Since glycosomes do not contain genetic information, all enzymes active in this compartment must be delivered there post-translationally. A group of enzymes called peroxins (small peroxisomal proteins, PEX #) govern this transport. Of these, PEX5 and PEX14 play an important role in this biochemical pathway because complex formation between them is necessary for the import of proteins from the cellular matrix into the glycosome. For this reason, it is postulated that preventing the formation of this complex, e.g. by means of a small-molecule drug-like substance, could be an interesting strategy to fight diseases caused by Trypanosoma, as well as a method of studying biochemical processes taking place in glycosomes. Interprotein interactions are among the most difficult molecular targets. As with many other protein interactions, the interaction of PEX14 with PEX5 is predominantly hydrophobic and aromatic in nature, with only two shallow, exposed binding pockets located over a large contact area. As a result, to be able to compete for binding sites on the PEX14 surface, a "conventional" "drug-like" chemical molecule would need to be strictly lipophilic in nature. This, in turn, implies difficulties in keeping the pharmacochemical parameters within the desired ranges. Therefore, there is a need to look for alternative strategies to inhibit this difficult molecular target, other than "classic" small molecule chemicals. The aim of this project is to try to use alpha helix mimetics, oxopiperazine derivatives, as new inhibitors of PEX14 and PEX5 protein interactions with high antiparasitic efficacy and appropriate pharmacochemical properties. A multidisciplinary approach to achieving this goal will be based on research methods such as chemical synthesis, computer-based ligand design based on protein structure, as well as biophysical and cellular assays. Lessons learned from these studies may be important not only for the design of future potential drugs against tropical diseases, but also for a better understanding of the biochemical processes involved in glycosomes.