Abstract
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.
Original language | English |
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Pages (from-to) | 229-233 |
Number of pages | 5 |
Journal | Nature |
Volume | 537 |
Issue number | 7619 |
Early online date | 8 Aug 2016 |
DOIs | |
Publication status | Published - 8 Sept 2016 |
Bibliographical note
© 2016 Macmillan Publishers Limited, part of Springer Nature. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details.Profiles
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Elmarie Myburgh
- The Hull York Medical School - Lecturer in Immunology & Infection, Former employee
Person: Academic