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Autor(en) / Beteiligte

Titel

Proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness

Ist Teil von

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2016

Link zum Volltext

Beschreibungen/Notizen

Chagas disease, leishmaniasis and sleeping sickness affect 20 million people worldwide and lead to more than 50,000 deaths annually. The diseases are caused by infection with the kinetoplastid parasites Trypanosoma cruzi, Leishmania spp. and Trypanosoma brucei spp., respectively. These parasites have similar biology and genomic sequence, suggesting that all three diseases could be cured with drugs that modulate the activity of a conserved parasite target. However, no such molecular targets or broad spectrum drugs have been identified to date. Here we describe a selective inhibitor of the kinetoplastid proteasome (GNF6702) with unprecedented in vivo efficacy, which cleared parasites from mice in all three models of infection. GNF6702 inhibits the kinetoplastid proteasome through a non-competitive mechanism, does not inhibit the mammalian proteasome or growth of mammalian cells, and is well-tolerated in mice. Our data provide genetic and chemical validation of the parasite proteasome as a promising therapeutic target for treatment of kinetoplastid infections, and underscore the possibility of developing a single class of drugs for these neglected diseases.

Sprache: Englisch
Identifikatoren: ISSN: 0028-0836
eISSN: 1476-4687
DOI: 10.1038/nature19339
Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5161665

Format: –
Schlagworte: Animals, Care and treatment, Cell growth, Chagas disease, Chagas Disease - drug therapy, Chagas Disease - parasitology, Chymotrypsin - antagonists & inhibitors, Chymotrypsin - metabolism, Disease Models, Animal, Drug therapy, Female, Humans, Inhibitor drugs, Inhibitory Concentration 50, Kinetoplastida - drug effects, Kinetoplastida - enzymology, Leishmaniasis, Leishmaniasis - drug therapy, Leishmaniasis - parasitology, Medical research, Medicine, Experimental, Mice, Molecular Structure, Molecular Targeted Therapy, Parasites, Parasitic diseases, Physiological aspects, Properties, Proteasome Endopeptidase Complex - drug effects, Proteasome inhibitors, Proteasome Inhibitors - adverse effects, Proteasome Inhibitors - classification, Proteasome Inhibitors - pharmacology, Proteasome Inhibitors - therapeutic use, Proteins, Protozoa, Pyrimidines - adverse effects, Pyrimidines - chemistry, Pyrimidines - pharmacology, Pyrimidines - therapeutic use, Species Specificity, Triazoles - adverse effects, Triazoles - chemistry, Triazoles - pharmacology, Triazoles - therapeutic use, Trypanosomiasis, Trypanosomiasis, African - drug therapy, Trypanosomiasis, African - parasitology

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