2. Academic Validation
  3. Development of novel PEX5-PEX14 protein-protein interaction (PPI) inhibitors based on an oxopiperazine template

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

  • Eur J Med Chem. 2023 Oct 5;258:115587. doi: 10.1016/j.ejmech.2023.115587.
Monika Marciniak 1,  Piotr Mróz 1,  Valeria Napolitano 2,  Vishal C Kalel 3,  Roberto Fino 2,  Emilia Pykacz 1,  Wolfgang Schliebs 3,  Oliver Plettenburg 4,  Ralf Erdmann 3,  Michael Sattler 5,  Grzegorz M Popowicz 5,  Maciej Dawidowski 6
Affiliations

Affiliations

  • 1 Department of Drug Technology and Pharmaceutical Biotechnology Medical University of Warsaw, Banacha 1, 02-097, Warszawa, Poland.
  • 2 Institute of Structural Biology, Molecular Targets and Therapeutics Center, Helmholtz Zentrum München, Ingolstädter Landstrasse 1, 85764, Neuherberg, Germany.
  • 3 Institute of Biochemistry and Pathobiochemistry, Department of Systems Biochemistry, Faculty of Medicine, Ruhr-University Bochum, 44780, Bochum, Germany.
  • 4 Institute of Medicinal Chemistry, Molecular Targets and Therapeutics Center, Helmholtz Zentrum München, Ingolstädter Landstr. 1, Neuherberg, 85764, Germany; Center of Biomolecular Drug Research (BMWZ), Institute of Organic Chemistry, Leibniz Universität Hannover, Schneiderberg 1b, Hannover, 30167, Germany.
  • 5 Institute of Structural Biology, Molecular Targets and Therapeutics Center, Helmholtz Zentrum München, Ingolstädter Landstrasse 1, 85764, Neuherberg, Germany; Bavarian NMR Center, Department of Bioscience, School of Natural Sciences, Technical University of Munich, Lichtenbergstrasse 4, 85747, Garching, Germany.
  • 6 Department of Drug Technology and Pharmaceutical Biotechnology Medical University of Warsaw, Banacha 1, 02-097, Warszawa, Poland. Electronic address: [email protected].
PMID: 37406382 DOI: 10.1016/j.ejmech.2023.115587
Abstract

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.

Keywords

Oxopiperazine; Peptidomimetics; Protein-protein interaction inhibitors; Structure-based drug design; Trypanocidal inhibitors; α-Helical mimetics.

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