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

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

Abstract

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.

Organisation(s)

Institute of Organic Chemistry

External Organisation(s)

Helmholtz Zentrum München - German Research Center for Environmental Health
Medical University of Warsaw
Ruhr-Universität Bochum
Jagiellonian University
ETH Zurich
Swiss Tropical Institute
University of Basel
Wroclaw University of Technology
Technical University of Munich (TUM)

Type

Article

Journal

Journal of medicinal chemistry

Volume

63

Pages

847-879

No. of pages

33

ISSN

0022-2623

Publication date

20.12.2019

Publication status

Published

Peer reviewed

Yes

ASJC Scopus subject areas

Molecular Medicine, Drug Discovery

Sustainable Development Goals

SDG 3 - Good Health and Well-being

Electronic version(s)

https://doi.org/10.1021/acs.jmedchem.9b01876 (Access: Open)