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Marciniak, M.* ; Mroz, P.* ; Napolitano, V. ; Kalel, V.C.* ; Fino, R. ; Pykacz, E.* ; Schliebs, W.* ; Plettenburg, O. ; Erdmann, R.* ; Sattler, M. ; Popowicz, G.M. ; Dawidowski, M.*

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

Eur. J. Med. Chem. 258:115587 (2023)
Verlagsversion DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Oxopiperazine ; Peptidomimetics ; Protein-protein Interaction Inhibitors ; Structure-based Drug Design ; Trypanocidal Inhibitors ; α-helical Mimetics; Import; Pex14; Design
Sprache englisch
Veröffentlichungsjahr 2023
HGF-Berichtsjahr 2023
ISSN (print) / ISBN 0223-5234
e-ISSN 1768-3254
Zeitschrift European Journal of Medicinal Chemistry
Quellenangaben Band: 258, Heft: , Seiten: , Artikelnummer: 115587 Supplement: ,
Verlag Elsevier
Verlagsort Amsterdam [u.a.]
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Structural Biology (STB)
Institute of Medicinal Chemistry (IMC)
POF Topic(s) 30203 - Molecular Targets and Therapies
Forschungsfeld(er) Enabling and Novel Technologies
PSP-Element(e) G-503000-001
G-506300-001
Förderungen Bundesministerium fuer Bildung and Forschung
Deutsche Forschungsgemeinschaft
Narodowe Centrum Nauki
DOI 10.1016/j.ejmech.2023.115587
WOS ID 001033294500001
Scopus ID 85163819403
PubMed ID 37406382
Erfassungsdatum 2023-10-18
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