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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2016-08-08

AUTHORS

Shilpi Khare, Advait S Nagle, Agnes Biggart, Yin H Lai, Fang Liang, Lauren C Davis, S Whitney Barnes, Casey J N Mathison, Elmarie Myburgh, Mu-Yun Gao, J Robert Gillespie, Xianzhong Liu, Jocelyn L Tan, Monique Stinson, Ianne C Rivera, Jaime Ballard, Vince Yeh, Todd Groessl, Glenn Federe, Hazel X Y Koh, John D Venable, Badry Bursulaya, Michael Shapiro, Pranab K Mishra, Glen Spraggon, Ansgar Brock, Jeremy C Mottram, Frederick S Buckner, Srinivasa P S Rao, Ben G Wen, John R Walker, Tove Tuntland, Valentina Molteni, Richard J Glynne, Frantisek Supek

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. More... »

PAGES

229-233

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nature19339

DOI

http://dx.doi.org/10.1038/nature19339

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1036903066

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/27501246


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