title: Proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness.
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.
authors: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors: Shilpi
authors: S
authors: Khare
authors: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors: Advait S
authors: AS
authors: Nagle
authors: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors: Agnes
authors: A
authors: Biggart
authors: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors: Yin H
authors: YH
authors: Lai
authors: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors: Fang
authors: F
authors: Liang
authors: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors: Lauren C
authors: LC
authors: Davis
authors: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors: S Whitney
authors: SW
authors: Barnes
authors: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors: Casey J N
authors: CJ
authors: Mathison
authors: 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.|Centre for Immunology and Infection, Department of Biology, University of York, Wentworth Way, Heslington, York YO10 5DD, UK.
authors: Elmarie
authors: E
authors: Myburgh
authors: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors: Mu-Yun
authors: MY
authors: Gao
authors: Department of Medicine, University of Washington, Seattle, Washington 98109, USA.
authors: J Robert
authors: JR
authors: Gillespie
authors: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors: Xianzhong
authors: X
authors: Liu
authors: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors: Jocelyn L
authors: JL
authors: Tan
authors: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors: Monique
authors: M
authors: Stinson
authors: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors: Ianne C
authors: IC
authors: Rivera
authors: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors: Jaime
authors: J
authors: Ballard
authors: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors: Vince
authors: V
authors: Yeh
authors: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors: Todd
authors: T
authors: Groessl
authors: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors: Glenn
authors: G
authors: Federe
authors: Novartis Institute for Tropical Diseases, 10 Biopolis Road, Singapore 138670.
authors: Hazel X Y
authors: HX
authors: Koh
authors: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors: John D
authors: JD
authors: Venable
authors: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors: Badry
authors: B
authors: Bursulaya
authors: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors: Michael
authors: M
authors: Shapiro
authors: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors: Pranab K
authors: PK
authors: Mishra
authors: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors: Glen
authors: G
authors: Spraggon
authors: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors: Ansgar
authors: A
authors: Brock
authors: 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.|Centre for Immunology and Infection, Department of Biology, University of York, Wentworth Way, Heslington, York YO10 5DD, UK.
authors: Jeremy C
authors: JC
authors: Mottram
authors: Department of Medicine, University of Washington, Seattle, Washington 98109, USA.
authors: Frederick S
authors: FS
authors: Buckner
authors: Novartis Institute for Tropical Diseases, 10 Biopolis Road, Singapore 138670.
authors: Srinivasa P S
authors: SP
authors: Rao
authors: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors: Ben G
authors: BG
authors: Wen
authors: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors: John R
authors: JR
authors: Walker
authors: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors: Tove
authors: T
authors: Tuntland
authors: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors: Valentina
authors: V
authors: Molteni
authors: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors: Richard J
authors: RJ
authors: Glynne
authors: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors: Frantisek
authors: F
authors: Supek
mesh_terms: D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy* / Q000469:parasitology; D002918:Chymotrypsin / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D016830:Kinetoplastida / Q000187:drug effects* / Q000201:enzymology*; D007896:Leishmaniasis / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects*; D061988:Proteasome Inhibitors / Q000009:adverse effects / Q000145:classification / Q000494:pharmacology* / Q000627:therapeutic use*; D011743:Pyrimidines / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013045:Species Specificity; D014230:Triazoles / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014353:Trypanosomiasis, African / Q000188:drug therapy* / Q000469:parasitology
chemical_list: C000614694:GNF6702; D061988:Proteasome Inhibitors; D011743:Pyrimidines; D014230:Triazoles; D002918:Chymotrypsin; D046988:Proteasome Endopeptidase Complex