Khare, S. et al. (2016) Proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness. Nature, 537(7619), pp. 229-233. (doi: 10.1038/nature19339) (PMID:27501246) (PMCID:PMC5161665)
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Abstract
Chagas disease, leishmaniasis and sleeping sickness affect 20 million people worldwide and lead to more than 50,000 deaths annually1. 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 target2. 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.
| Item Type: | Articles (Letter) |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Myburgh, Dr Elmarie and Mottram, Professor Jeremy |
| Authors: | Khare, S., Nagle, A. S., Biggart, A., Lai, Y. H., Liang, F., Davis, L. C., Barnes, S. W., Mathison, C. J.N., Myburgh, E., Gao, M.-Y., Gillespie, J. R., Liu, X., Tan, J. L., Stinson, M., Rivera, I. C., Ballard, J., Yeh, V., Groessl, T., Federe, G., Koh, H. X.Y., Venable, J. D., Bursulaya, B., Shapiro, M., Mishra, P. K., Spraggon, G., Brock, A., Mottram, J. C., Buckner, F. S., Rao, S. P.S., Wen, B. G., Walker, J. R., Tuntland, T., Molteni, V., Glynne, R. J., and Supek, F. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
| Journal Name: | Nature |
| Publisher: | Nature Publishing Group |
| ISSN: | 0028-0836 |
| ISSN (Online): | 1476-4687 |
| Published Online: | 08 August 2016 |
| Copyright Holders: | Copyright © 2016 Macmillan Publishers Limited |
| First Published: | First published in Nature 537(7619):229-233 |
| Publisher Policy: | Reproduced in accordance with the copyright policy of the publisher |
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