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J Med Chem. 2020 Jan 23;63(2):847-879. doi: 10.1021/acs.jmedchem.9b01876. Epub 2020 Jan 6.

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

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Center for Integrated Protein Science Munich at Chair of Biomolecular NMR, Department Chemie , Technische Universität München , Lichtenbergstrasse 4 , 85747 Garching , Germany.
Department of Drug Technology and Pharmaceutical Biotechnology , Medical University of Warsaw , Banacha 1 , 02-097 Warszawa , Poland.
Institute of Biochemistry and Pathobiochemistry, Department of Systems Biochemistry, Faculty of Medicine , Ruhr-University Bochum , 44780 Bochum , Germany.
Faculty of Biochemistry, Biophysics and Biotechnology , Jagiellonian University , Gronostajowa 7 , Krakow 30-387 , Poland.
Małopolska Center of Biotechnology , Jagiellonian University in Kraków , Gronostajowa 7 , Kraków 30-387 , Poland.
Swiss Tropical and Public Health Institute , Socinstrasse 57 , 4051 Basel , Switzerland.
University of Basel , 4001 Basel , Switzerland.
Department of Biochemistry, Faculty of Chemistry , Wrocław University of Science and Technology , Wybrzeże Wyspiańskiego 27 , 50-370 Wrocław , Poland.
Institute of Organic Chemistry , Leibniz Universität Hannover , Schneiderberg 1b , Hannover 30167 , Germany.


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.

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