title: Inhibitors of PEX14 disrupt protein import into glycosomes and killTrypanosomaparasites.
abstract: The parasitic protists of theTrypanosomagenus 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 killTrypanosomaby 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 theTrypanosomasuitable for the development of new therapies against trypanosomiases and provide the structural basis for their development.
authors.affiliation: Institute of Structural Biology, Helmholtz Zentrum München, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.|Center for Integrated Protein Science Munich at Chair of Biomolecular NMR, Department Chemie, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany.
authors.forename: M
authors.identifier: 0000-0002-7262-5718
authors.initials: M
authors.lastname: Dawidowski
authors.affiliation: Institute of Structural Biology, Helmholtz Zentrum München, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.|Center for Integrated Protein Science Munich at Chair of Biomolecular NMR, Department Chemie, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany.
authors.forename: L
authors.identifier: 0000-0001-8931-8901
authors.initials: L
authors.lastname: Emmanouilidis
authors.affiliation: Institute of Biochemistry and Pathobiochemistry, Department of Systems Biochemistry, Faculty of Medicine, Ruhr University Bochum, 44780 Bochum, Germany.
authors.forename: V C
authors.identifier: 0000-0001-6023-7454
authors.initials: VC
authors.lastname: Kalel
authors.affiliation: CEITEC, Central European Institute of Technology, Masaryk University, Kamenice 5, 62500 Brno, Czech Republic.
authors.forename: K
authors.identifier: 0000-0003-0948-813X
authors.initials: K
authors.lastname: Tripsianes
authors.affiliation: Assay Development and Screening Platform, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.
authors.forename: K
authors.identifier: 0000-0001-9428-9877
authors.initials: K
authors.lastname: Schorpp
authors.affiliation: Assay Development and Screening Platform, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.
authors.forename: K
authors.identifier: 0000-0001-8727-2575
authors.initials: K
authors.lastname: Hadian
authors.affiliation: Swiss Tropical and Public Health Institute, Socinstrasse 57, 4051 Basel, Switzerland.|University of Basel, 4001 Basel, Switzerland.
authors.forename: M
authors.identifier: 0000-0003-1785-7302
authors.initials: M
authors.lastname: Kaiser
authors.affiliation: Swiss Tropical and Public Health Institute, Socinstrasse 57, 4051 Basel, Switzerland.|University of Basel, 4001 Basel, Switzerland.
authors.forename: P
authors.identifier: 0000-0003-3122-1941
authors.initials: P
authors.lastname: Mäser
authors.affiliation: Institute of Structural Biology, Helmholtz Zentrum München, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Kolonko
authors.affiliation: New York University School of Medicine, Department of Microbiology, 341 East 25th Street, Room 513, New York, NY 10010, USA.
authors.forename: S
authors.identifier: 0000-0001-6643-4897
authors.initials: S
authors.lastname: Tanghe
authors.affiliation: New York University School of Medicine, Department of Microbiology, 341 East 25th Street, Room 513, New York, NY 10010, USA.
authors.forename: A
authors.initials: A
authors.lastname: Rodriguez
authors.affiliation: Institute of Biochemistry and Pathobiochemistry, Department of Systems Biochemistry, Faculty of Medicine, Ruhr University Bochum, 44780 Bochum, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Schliebs
authors.affiliation: 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.
authors.forename: R
authors.identifier: 0000-0001-8380-0342
authors.initials: R
authors.lastname: Erdmann
authors.affiliation: 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.|Center for Integrated Protein Science Munich at Chair of Biomolecular NMR, Department Chemie, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany.
authors.forename: M
authors.identifier: 0000-0002-1594-0527
authors.initials: M
authors.lastname: Sattler
authors.affiliation: 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.|Center for Integrated Protein Science Munich at Chair of Biomolecular NMR, Department Chemie, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany.
authors.forename: G M
authors.identifier: 0000-0003-2818-7498
authors.initials: GM
authors.lastname: Popowicz
mesh_terms: D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy; D015195:Drug Design; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008830:Microbodies / Q000187:drug effects / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D000074435:Peroxisome-Targeting Signal 1 Receptor; D020675:Peroxisomes / Q000187:drug effects / Q000378:metabolism; D000072417:Protein Domains; D021381:Protein Transport / Q000187:drug effects; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014346:Trypanosoma brucei brucei / Q000187:drug effects*; D014353:Trypanosomiasis, African / Q000188:drug therapy
chemical_list: D008565:Membrane Proteins; C468927:PEX14 protein, Trypanosoma brucei; C000614264:PEX5 protein, human; D000074435:Peroxisome-Targeting Signal 1 Receptor; D015800:Protozoan Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D054852:Small Molecule Libraries; D014344:Trypanocidal Agents