Inhibitors of glycosomal protein import provide new leads against trypanosomiasis
Authors:Vishal C. Kalel1, Leonidas Emmanouilidis2,3, Maciej Dawidowski2,3,4, Wolfgang Schliebs1, Michael Sattler2,3, Grzegorz M. Popowicz2,3, Ralf Erdmann1
doi: 10.15698/mic2017.07.581
Volume 4, pp. 229 to 232, published 03/07/2017.
1 Institute of Biochemistry and Pathobiochemistry, Department of Systems Biochemistry, Faculty of Medicine, Ruhr University Bochum, 44780 Bochum, Germany.
2 Institute of Structural Biology, Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
3 Center for Integrated Protein Science Munich at Chair of Biomolecular NMR, Department Chemie, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany.
4 Chair and Department of Drug Technology and Pharmaceutical Biotechnology, Medical University of Warsaw, Banacha 1, 02-097 Warszawa, Poland.
Keywords:
Trypanosoma, glycosomes, PEX, protein-protein interactions, small molecule inhibitors.
Corresponding Author(s):
Conflict of interest statement:
Helmholtz Zentrum München has a patent application (WO2016038045) for chemical matter published in the original study, which is reviewed here.
Please cite this article as:
Vishal C. Kalel, Leonidas Emmanouilidis, Maciej Dawidowski, Wolfgang Schliebs, Michael Sattler, Grzegorz M. Popowicz and Ralf Erdmann (2017). Inhibitors of glycosomal protein import provide new leads against trypanosomiasis. Microbial Cell 4(7):229-232. doi: 10.15698/mic2017.07.581
© 2017 Kalel et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.
Abstract:
Vector-borne trypanosomatid parasite infections in tropical and sub-tropical countries constitute a major threat to humans and livestock. Trypanosoma brucei parasites are transmitted by tsetse fly and lead to African sleeping sickness in humans and Nagana in cattle. In Latin American countries, Trypanosoma cruzi infections spread by triatomine kissing bugs lead to Chagas disease. Various species of Leishmania transmitted to humans by phlebotomine sandflies manifest in a spectrum of diseases termed Leishmaniasis. 20 million people are currently infected with trypanosomatid parasites, leading to over 30,000 deaths annually and half billion people at risk of the infection. It is estimated that 300,000 Chagas infected people reside in the United States and 100,000 in Europe. Glycosomes are peroxisome-like organelles found only in trypanosomatids. Glycolysis occurs in the cytosol in all other organisms, but glycolytic enzymes and other metabolic pathways are compartmentalized inside glycosomes in trypanosomatids. Glycosomes are essential for the parasite survival and hence thought to be an attractive drug target. Our recent study [Dawidowski et al. Science (2017)] is the first to report small molecule inhibitors of glycosomal protein import. Using structure-based drug design, we developed small molecule inhibitors of the Trypanosoma PEX5-PEX14 protein-protein interaction that disrupt glycosomal protein import and kill the parasites. Oral treatment of T. brucei infected mice with PEX14 inhibitor significantly reduced the parasite levels with no adverse effect on mice. The study provides the grounds for further development of the glycosome inhibitors into clinical candidates and validates the parasite protein-protein interactions as drug targets.