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Dawidowski, Maciej [Author]; Kalel, Vishal C. [Author]; Napolitano, Valeria [Author]; Fino, Roberto [Author]; Schorpp, Kenji [Author]; Emmanouilidis, Leonidas [Author]; Lenhart, Dominik [Author]; Ostertag, Michael [Author]; Kaiser, Marcel [Author]; Kolonko, Marta [Author]; Tippler, Bettina [Author]; Schliebs, Wolfgang [Author]; Dubin, Grzegorz [Author]; Mäser, Pascal [Author]; Tetko, Igor V. [Author]; Hadian, Kamyar [Author]; Plettenburg, Oliver [Author]; Erdmann, Ralf [Author]; Sattler, Michael [Author]; Popowicz, Grzegorz M. [Author]

Structure-Activity Relationship in Pyrazolo[4,3- c]pyridines, First Inhibitors of PEX14-PEX5 Protein-Protein Interaction with Trypanocidal Activity - [published Version]

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  • Media type: Text; E-Article
  • Title: Structure-Activity Relationship in Pyrazolo[4,3- c]pyridines, First Inhibitors of PEX14-PEX5 Protein-Protein Interaction with Trypanocidal Activity
  • Contributor: Dawidowski, Maciej [Author]; Kalel, Vishal C. [Author]; Napolitano, Valeria [Author]; Fino, Roberto [Author]; Schorpp, Kenji [Author]; Emmanouilidis, Leonidas [Author]; Lenhart, Dominik [Author]; Ostertag, Michael [Author]; Kaiser, Marcel [Author]; Kolonko, Marta [Author]; Tippler, Bettina [Author]; Schliebs, Wolfgang [Author]; Dubin, Grzegorz [Author]; Mäser, Pascal [Author]; Tetko, Igor V. [Author]; Hadian, Kamyar [Author]; Plettenburg, Oliver [Author]; Erdmann, Ralf [Author]; Sattler, Michael [Author]; Popowicz, Grzegorz M. [Author]
  • imprint: Washington, DC : ACS, 2019
  • Published in: Journal of Medicinal Chemistry (formerly: Journal of Medicinal and Pharmaceutical Chemistry) 63 (2020), Nr. 2 ; Journal of Medicinal Chemistry (formerly: Journal of Medicinal and Pharmaceutical Chemistry)
  • Issue: published Version
  • Language: English
  • DOI: https://doi.org/10.15488/16445; https://doi.org/10.1021/acs.jmedchem.9b01876
  • ISSN: 0022-2623
  • Keywords: Crystallography ; X-Ray ; Humans ; Drug Design ; Magnetic Resonance Spectroscopy ; Animals
  • Origination:
  • Footnote: Diese Datenquelle enthält auch Bestandsnachweise, die nicht zu einem Volltext führen.
  • Description: Trypanosoma protists are pathogens leading to a spectrum of devastating infectious diseases. The range of available chemotherapeutics against Trypanosoma is limited, and the existing therapies are partially ineffective and cause serious adverse effects. Formation of the PEX14-PEX5 complex is essential for protein import into the parasites' glycosomes. This transport is critical for parasite metabolism and failure leads to mislocalization of glycosomal enzymes, with fatal consequences for the parasite. Hence, inhibiting the PEX14-PEX5 protein-protein interaction (PPI) is an attractive way to affect multiple metabolic pathways. Herein, we have used structure-guided computational screening and optimization to develop the first line of compounds that inhibit PEX14-PEX5 PPI. The optimization was driven by several X-ray structures, NMR binding data, and molecular dynamics simulations. Importantly, the developed compounds show significant cellular activity against Trypanosoma, including the human pathogen Trypanosoma brucei gambiense and Trypanosoma cruzi parasites.
  • Access State: Open Access
  • Rights information: Attribution - Non Commercial - No Derivs (CC BY-NC-ND)