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Inhibitors of PEX14 disrupt protein import into glycosomes and kill Trypanosoma parasites.
Science 355, 1416-1420 (2017)
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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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37.205
7.688
1
43
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Publication type
Article: Journal article
Document type
Scientific Article
Language
english
Publication Year
2017
HGF-reported in Year
2017
ISSN (print) / ISBN
0036-8075
e-ISSN
1095-9203
Journal
Science
Quellenangaben
Volume: 355,
Issue: 6332,
Pages: 1416-1420
Publisher
American Association for the Advancement of Science (AAAS)
Reviewing status
Peer reviewed
Institute(s)
Institute of Structural Biology (STB)
Institute of Molecular Toxicology and Pharmacology (TOX)
Institute of Molecular Toxicology and Pharmacology (TOX)
POF-Topic(s)
30203 - Molecular Targets and Therapies
Research field(s)
Enabling and Novel Technologies
PSP Element(s)
G-503000-001
G-505293-001
G-505293-001
Scopus ID
85016811904
PubMed ID
28360328
Erfassungsdatum
2017-04-04