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Science. 2017 Mar 31;355(6332):1416-1420. doi: 10.1126/science.aal1807.

Inhibitors of PEX14 disrupt protein import into glycosomes and kill Trypanosoma parasites.

Author information

1
Institute of Structural Biology, Helmholtz Zentrum München, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.
2
Center for Integrated Protein Science Munich at Chair of Biomolecular NMR, Department Chemie, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany.
3
Institute of Biochemistry and Pathobiochemistry, Department of Systems Biochemistry, Faculty of Medicine, Ruhr University Bochum, 44780 Bochum, Germany.
4
CEITEC, Central European Institute of Technology, Masaryk University, Kamenice 5, 62500 Brno, Czech Republic.
5
Assay Development and Screening Platform, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.
6
Swiss Tropical and Public Health Institute, Socinstrasse 57, 4051 Basel, Switzerland.
7
University of Basel, 4001 Basel, Switzerland.
8
New York University School of Medicine, Department of Microbiology, 341 East 25th Street, Room 513, New York, NY 10010, USA.
9
Institute of Biochemistry and Pathobiochemistry, Department of Systems Biochemistry, Faculty of Medicine, Ruhr University Bochum, 44780 Bochum, Germany. grzegorz.popowicz@helmholtz-muenchen.de sattler@helmholtz-muenchen.de ralf.erdmann@rub.de.
10
Institute of Structural Biology, Helmholtz Zentrum München, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany. grzegorz.popowicz@helmholtz-muenchen.de sattler@helmholtz-muenchen.de ralf.erdmann@rub.de.

Abstract

The parasitic protists of the Trypanosoma genus infect humans and domestic mammals, causing severe mortality and huge economic losses. The most threatening trypanosomiasis is Chagas disease, affecting up to 12 million people in the Americas. We report a way to selectively kill Trypanosoma by blocking glycosomal/peroxisomal import that depends on the PEX14-PEX5 protein-protein interaction. We developed small molecules that efficiently disrupt the PEX14-PEX5 interaction. This results in mislocalization of glycosomal enzymes, causing metabolic catastrophe, and it kills the parasite. High-resolution x-ray structures and nuclear magnetic resonance data enabled the efficient design of inhibitors with trypanocidal activities comparable to approved medications. These results identify PEX14 as an "Achilles' heel" of the Trypanosoma suitable for the development of new therapies against trypanosomiases and provide the structural basis for their development.

PMID:
28360328
DOI:
10.1126/science.aal1807
[Indexed for MEDLINE]

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