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Dawidowski, M. ; Kalel, V.C.* ; Napolitano, V.* ; Fino, R. ; Schorpp, K.K. ; Emmanouilidis, L. ; Lenhart, D. ; Ostertag, M.S. ; Kaiser, M.* ; Kolonko, M. ; Tippler, B.* ; Schliebs, W.* ; Dubin, G.* ; Mäser, P.* ; Tetko, I.V. ; Hadian, K. ; Plettenburg, O. ; Erdmann, R.* ; Sattler, M. ; Popowicz, G.M.

Structure-activity relationship in pyrazolo[4,3-c]pyridines, first inhibitors of PEX14-PEX5 Protein-Protein Interaction (PPI) with trypanocidal activity.

J. Med. Chem. 63, 847-879 (2020)
Verlagsversion DOI
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Small-molecule Inhibitors; Trypanosoma-brucei; Potential Functions; Sleeping Sickness; Drug-resistance; Chagas-disease; Nitro Drugs; Import; Compartmentation; Fexinidazole
ISSN (print) / ISBN 0022-2623
e-ISSN 1520-4804
Quellenangaben Band: 63, Heft: 2, Seiten: 847-879 Artikelnummer: , Supplement: ,
Verlag American Chemical Society (ACS)
Verlagsort 1155 16th St, Nw, Washington, Dc 20036 Usa
Begutachtungsstatus Peer reviewed