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

Dawidowski, M. and Emmanouilidis, L. and Kalel, V. C. and Tripsianes, K. and Schorpp, K. and Hadian, K. and Kaiser, M. and Mäser, P. and Kolonko, M. and Tanghe, S. and Rodriguez, A. and Schliebs, W. and Erdmann, R. and Sattler, M. and Popowicz, G. M.. (2017) Inhibitors of PEX14 disrupt protein import into glycosomes and kill Trypanosoma parasites. Science, 355 (6332). pp. 1416-1420.

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Official URL: http://edoc.unibas.ch/54933/

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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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Kaiser, Marcel and Mäser, Pascal
Item Type:Article, refereed
Publisher:American Association for the Advancement of Science
ISSN:0036-8075
e-ISSN:1095-9203
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:29 May 2017 12:38
Deposited On:29 May 2017 12:38

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