Development of novel PEX5-PEX14 protein-protein interaction (PPI) inhibitors based on an oxopiperazine template

Protein-protein interactions (PPIs) constitute an important but challenging class of molecular targets for small molecules. The PEX5-PEX14 PPI has been shown to play a critical role in glycosome biogenesis and its disruption impairs the metabolism in Trpanosoma parasites, eventually leading to their death. Therefore, this PPI is a po-tential molecular target for new drugs against diseases caused by Trypanosoma infections. Here, we report a new class of peptidomimetic scaffolds to target the PEX5-PEX14 PPI. The molecular design was based on an oxopi-perazine template for the a-helical mimetics. A structural simplification along with modifications of the central oxopiperazine scaffold and addressing the lipophilic interactions led to the development of peptidomimetics that inhibit PEX5-TbPEX14 PPI and display cellular activity against T. b. brucei. This approach provides an alternative approach towards the development of trypanocidal agents and may be generally useful for the design of helical mimetics as PPI inhibitors.

Automated summary

Protein-protein interactions (PPIs) are important targets for small molecule drugs, but can be challenging to inhibit. In this study, a new class of peptidomimetic scaffolds was developed to target the PEX5-PEX14 PPI, which plays a critical role in glycosome biogenesis and is a potential target for drugs against Trypanosoma infections. The designed peptidomimetics inhibited the PEX5-TbPEX14 PPI and exhibited cellular activity against T. b. brucei, providing a promising approach for the development of trypanocidal agents and helical mimetics as PPI inhibitors.