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.

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This work was supported in part by grants from the Wellcome Trust (091038/Z/09/Z to R.J.G. and F.S., and 104976/Z/14/Z, 104111/15/Z to J.C.M. and E.M.) and NIH (AI106850 to F.S.B.). We thank S. Croft, R. Don, L. Gredsted, A. Hudson and J. Mendlein for discussions, R. Tarleton for T. cruzi CL strain, and G. Cross for T. brucei Lister 427 strain. We thank A. Kreusch for help with proteasome purification, and F. Luna for help with T. cruzi whole-genome sequencing. We acknowledge technical assistance of O. Faghih in generating the plasmids for ectopic expression of PSMB4 in T. cruzi, R. Ritchie for IVIS in vivo imaging, and A. Mak, J. Matzen and P. Anderson for execution of high-throughput screens. We thank J. Isbell and T. Hollenbeck for profiling GNF6702 in ADME assays.

Author information

Author notes

    • Shilpi Khare
    •  & Advait S. Nagle

    These authors contributed equally to this work.


  1. Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA

    • Shilpi Khare
    • , Advait S. Nagle
    • , Agnes Biggart
    • , Yin H. Lai
    • , Fang Liang
    • , Lauren C. Davis
    • , S. Whitney Barnes
    • , Casey J. N. Mathison
    • , Mu-Yun Gao
    • , Xianzhong Liu
    • , Jocelyn L. Tan
    • , Monique Stinson
    • , Ianne C. Rivera
    • , Jaime Ballard
    • , Vince Yeh
    • , Todd Groessl
    • , Glenn Federe
    • , John D. Venable
    • , Badry Bursulaya
    • , Michael Shapiro
    • , Pranab K. Mishra
    • , Glen Spraggon
    • , Ansgar Brock
    • , Ben G. Wen
    • , John R. Walker
    • , Tove Tuntland
    • , Valentina Molteni
    • , Richard J. Glynne
    •  & Frantisek Supek
  2. Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK

    • Elmarie Myburgh
    •  & Jeremy C. Mottram
  3. Centre for Immunology and Infection, Department of Biology, University of York, Wentworth Way, Heslington, York YO10 5DD, UK

    • Elmarie Myburgh
    •  & Jeremy C. Mottram
  4. Department of Medicine, University of Washington, Seattle, Washington 98109, USA

    • J. Robert Gillespie
    •  & Frederick S. Buckner
  5. Novartis Institute for Tropical Diseases, 10 Biopolis Road, Singapore 138670.

    • Hazel X. Y. Koh
    •  & Srinivasa P. S. Rao


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A.B., F.L., C.J.N.M., P.K.M., A.S.N., J.L.T. and V.Y. designed chemical analogues, and performed chemical synthesis and purification of synthesized analogues. F.S.B., J.B., J.R.G., S.K., H.X.Y.K., Y.H.L., S.P.S.R., F.S. and X.L. conducted and analysed data from in vitro growth-inhibition assays. L.C.D., X.L., J.C.M., E.M., I.C.R., S.P.S.R., M.S., F.S. and B.G.W. conducted and analysed data from in vivo efficacy assays. J.B., M.-Y.G., S.K. and F.S. conducted proteasome purification, proteasome inhibition assays and biochemical data analysis. S.W.B., G.F., S.K., F.S. and J.R.W. designed, conducted and analysed experiments resulting in identification of proteasome resistance mutations. G.S. and B.B. built the homology model of T. cruzi proteasome structure and performed GNF6702 docking. A.B. and J.D.V. analysed T. cruzi proteasome by mass spectrometry. A.N., T.G., M.S., F.S. and T.T. designed, conducted, and analysed PK data. A.N. and V.M. led the chemistry team. F.S. led the biology team. R.J.G. and F.S. supervised and led the overall project, and led the writing of the manuscript. All authors contributed to writing of the manuscript.

Competing interests

Patents related to this work have been filed (WO 2015/095477 A1, WO 2014/151784 A1, WO 2014/151729). Several authors own shares of Novartis.

Corresponding author

Correspondence to Frantisek Supek.

Reviewer Information

Nature thanks M. PhilIips, S. Schreiber and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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