The cell cycle as a therapeutic target against Trypanosoma brucei

Hesperadin inhibits Aurora kinase-1 and blocks mitotic progression in bloodstream forms

Neal Jetton, Karen G. Rothberg, James G. Hubbard, John Wise, Yan Li, Haydn L. Ball, Larry Ruben

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Aurora kinase family members co-ordinate a range of events associated with mitosis and cytokinesis. Anti-cancer therapies are currently being developed against them. Here, we evaluate whether Aurora kinase-1 (TbAUK1) from pathogenic Trypanosoma brucei might be targeted in anti-parasitic therapies as well. Conditional knockdown of TbAUK1 within infected mice demonstrated its essential contribution to infection. An in vitro kinase assay was developed which used recombinant trypanosome histone H3 as a substrate. Tandem mass spectroscopy identified a novel phosphorylation site in the carboxyl-tail of recombinant trypanosome histone H3. Hesperadin, an inhibitor of human Aurora B, prevented the phosphorylation of substrate with IC50 of 40 nM. Growth of cultured bloodstream forms was also sensitive to Hesperadin (IC50 of 50 nM). Hesperadin blocked nuclear division and cytokinesis but not other aspects of the cell cycle. Consequently, growth arrested cells accumulated multiple kinetoplasts, flagella and nucleoli, similar to the effects of RNAi-dependent knockdown of TbAUK1 in cultured bloodstream forms cells. Molecular models predicted high-affinity binding of Hesperadin to both conserved and novel sites in TbAUK1. Collectively, these data demonstrate that cell cycle progression is essential for infections with T. brucei and that parasite Aurora kinases can be targeted with small-molecule inhibitors.

Original languageEnglish (US)
Pages (from-to)442-458
Number of pages17
JournalMolecular Microbiology
Volume72
Issue number2
DOIs
StatePublished - Apr 2009

Fingerprint

Aurora Kinases
Trypanosoma brucei brucei
Cell Cycle
Cytokinesis
Trypanosomiasis
Histones
Inhibitory Concentration 50
Phosphorylation
Cell Nucleus Division
Molecular Models
Flagella
Therapeutics
Growth
RNA Interference
Infection
Mitosis
Tail
Mass Spectrometry
Parasites
Phosphotransferases

ASJC Scopus subject areas

  • Molecular Biology
  • Microbiology

Cite this

The cell cycle as a therapeutic target against Trypanosoma brucei : Hesperadin inhibits Aurora kinase-1 and blocks mitotic progression in bloodstream forms. / Jetton, Neal; Rothberg, Karen G.; Hubbard, James G.; Wise, John; Li, Yan; Ball, Haydn L.; Ruben, Larry.

In: Molecular Microbiology, Vol. 72, No. 2, 04.2009, p. 442-458.

Research output: Contribution to journalArticle

Jetton, Neal ; Rothberg, Karen G. ; Hubbard, James G. ; Wise, John ; Li, Yan ; Ball, Haydn L. ; Ruben, Larry. / The cell cycle as a therapeutic target against Trypanosoma brucei : Hesperadin inhibits Aurora kinase-1 and blocks mitotic progression in bloodstream forms. In: Molecular Microbiology. 2009 ; Vol. 72, No. 2. pp. 442-458.
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