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

• Published in: European journal of medicinal chemistry Vol. 258; p. 115587
• Main Authors: Marciniak, Monika, Mróz, Piotr, Napolitano, Valeria, Kalel, Vishal C., Fino, Roberto, Pykacz, Emilia, Schliebs, Wolfgang, Plettenburg, Oliver, Erdmann, Ralf, Sattler, Michael, Popowicz, Grzegorz M., Dawidowski, Maciej
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 05.10.2023
• Subjects: Membrane Proteins - metabolism; Oxopiperazine; Peptidomimetics; Protein-protein interaction inhibitors; Structure-based drug design; Trypanocidal inhibitors; α-Helical mimetics; Protein-protein interaction inhibitors; Structure-based drug design; Oxopiperazine; Peptidomimetics; α-Helical mimetics; Trypanocidal inhibitors
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115587

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 potential 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 oxopiperazine template for the α-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. [Display omitted] •First peptidomimetic inhibitors of PEX5-PEX14 PPI were developed.•An oxopiperazine template was used to mimic the native binding mode of PEX5 to PEX14.•The central scaffold was re-designed for affinity gain.•Low micromolar activity against T. b. brucei was achieved.