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Parasite proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness

Khare, Shilpi and Nagle, Advait and Lai, Yin and Liang, Fang and Davis, Lauren and Barnes, Whitney and Mathison, Casey and Myburgh, Elamrie and Gao, Mu-Yun and Gillespie, Robert and Liu, Xianzhong and Tan, Jocelyn and Stinson, Monique and Rivera, Ianne and Ballard, Jaime and Yeh, Vince and Groessl, Todd and Federe, Glenn and Koh, Hazel and Venable, John and Bursulaya, Badry and Shapiro, Michael and Mishra, Pranab and Spraggon, Glen and Brock, Ansgar and Mottram, Jeremy and Buckner, Frederick and Rao, Srinivasa P.S. and Wen, Ben and Walker, John and Tuntland, Tove and Molteni, Valentina and Glynne, Richard and Supek, Frantisek (2016) Parasite proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness. Nature, 537 (7619). pp. 229-233. ISSN 0028-0836

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: Article
Keywords: proteasome, leishmaniasis, Chagas disease, sleeping sickness, drug target
Date Deposited: 17 Sep 2016 00:45
Last Modified: 17 Sep 2016 00:45
URI: https://oak.novartis.com/id/eprint/27938

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