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

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posted on 06.01.2020, 13:34 authored by Maciej Dawidowski, Vishal C. Kalel, Valeria Napolitano, Roberto Fino, Kenji Schorpp, Leonidas Emmanouilidis, Dominik Lenhart, Michael Ostertag, Marcel Kaiser, Marta Kolonko, Bettina Tippler, Wolfgang Schliebs, Grzegorz Dubin, Pascal Mäser, Igor V. Tetko, Kamyar Hadian, Oliver Plettenburg, Ralf Erdmann, Michael Sattler, Grzegorz M. Popowicz
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.