title: Lysine acetylation in sexual stage malaria parasites is a target for antimalarial small molecules.
abstract: Therapies to prevent transmission of malaria parasites to the mosquito vector are a vital part of the global malaria elimination agenda. Primaquine is currently the only drug with such activity; however, its use is limited by side effects. The development of transmission-blocking strategies requires an understanding of sexual stage malaria parasite (gametocyte) biology and the identification of new drug leads. Lysine acetylation is an important posttranslational modification involved in regulating eukaryotic gene expression and other essential processes. Interfering with this process with histone deacetylase (HDAC) inhibitors is a validated strategy for cancer and other diseases, including asexual stage malaria parasites. Here we confirm the expression of at least one HDAC protein in Plasmodium falciparum gametocytes and show that histone and nonhistone protein acetylation occurs in this life cycle stage. The activity of the canonical HDAC inhibitors trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA; Vorinostat) and a panel of novel HDAC inhibitors on early/late-stage gametocytes and on gamete formation was examined. Several compounds displayed early/late-stage gametocytocidal activity, with TSA being the most potent (50% inhibitory concentration, 70 to 90 nM). In contrast, no inhibitory activity was observed in P. falciparum gametocyte exflagellation experiments. Gametocytocidal HDAC inhibitors caused hyperacetylation of gametocyte histones, consistent with a mode of action targeting HDAC activity. Our data identify HDAC inhibitors as being among a limited number of compounds that target both asexual and sexual stage malaria parasites, making them a potential new starting point for gametocytocidal drug leads and valuable tools for dissecting gametocyte biology.
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia School of Medicine, University of Queensland, Herston, Queensland, Australia.
authors.forename: Katharine
authors.initials: K
authors.lastname: Trenholme
authors.affiliation: Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University, Duesseldorf, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Marek
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Duffy
authors.affiliation: Institute of Molecular Biotechnology, RWTH Aachen University, Aachen, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pradel
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia.
authors.forename: Gillian
authors.initials: G
authors.lastname: Fisher
authors.affiliation: Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University, Duesseldorf, Germany.
authors.forename: Finn K
authors.initials: FK
authors.lastname: Hansen
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia.
authors.forename: Tina S
authors.initials: TS
authors.lastname: Skinner-Adams
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia School of Medicine, University of Queensland, Herston, Queensland, Australia.
authors.forename: Alice
authors.initials: A
authors.lastname: Butterworth
authors.affiliation: Institute of Molecular Biotechnology, RWTH Aachen University, Aachen, Germany.
authors.forename: Che Julius
authors.initials: CJ
authors.lastname: Ngwa
authors.affiliation: Institute of Molecular Biotechnology, RWTH Aachen University, Aachen, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Moecking
authors.affiliation: School of Botany, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Goodman
authors.affiliation: School of Botany, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: McFadden
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia.
authors.forename: Subathdrage D M
authors.initials: SD
authors.lastname: Sumanadasa
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, St. Lucia, Queensland, Australia.
authors.forename: David P
authors.initials: DP
authors.lastname: Fairlie
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia.
authors.forename: Vicky M
authors.initials: VM
authors.lastname: Avery
authors.affiliation: Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University, Duesseldorf, Germany thomas.kurz@uni-duesseldorf.de k.andrews@griffith.edu.au.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kurz
authors.affiliation: Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia thomas.kurz@uni-duesseldorf.de k.andrews@griffith.edu.au.
authors.forename: Katherine T
authors.initials: KT
authors.lastname: Andrews
mesh_terms: D000107:Acetylation / Q000187:drug effects*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D005407:Flagella / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D008239:Lysine / Q000378:metabolism*; D010961:Plasmodium / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism*; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D054852:Small Molecule Libraries
chemical_list: D000962:Antimalarials; D056572:Histone Deacetylase Inhibitors; D054852:Small Molecule Libraries; D000255:Adenosine Triphosphate; D006655:Histone Deacetylases; D008239:Lysine
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