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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)
Postprint DOI PMC
Open Access Green
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
Korrespondenzautor
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
Zeitschrift Journal of Medicinal Chemistry
Quellenangaben Band: 63, Heft: 2, Seiten: 847-879 Artikelnummer: , Supplement: ,
Verlag American Chemical Society (ACS)
Verlagsort 1155 16th St, Nw, Washington, Dc 20036 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Structural Biology (STB)
Institute of Molecular Toxicology and Pharmacology (TOXI)
Institute of Medicinal Chemistry (IMC)