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

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Science  31 Mar 2017:
Vol. 355, Issue 6332, pp. 1416-1420
DOI: 10.1126/science.aal1807

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Small molecules to target parasite organelle

The glycosome is a peroxisome-like organelle that packages glycolytic enzymes of the parasites that cause sleeping sickness, Chagas disease, and leishmaniases. Dawidowski et al. designed small-molecule inhibitors to disrupt interactions between two of the proteins involved in peroxisome biogenesis (PEX5 and PEX14), which permit import of glycosomal matrix proteins from the cytoplasm. The small peptide–mimicking molecules kill the trypanosome parasites by causing metabolic collapse without interfering with human PEX homologs. Preliminary studies in mice confirmed an antiparasitic effect.

Science, this issue p. 1416

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.

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