Lysine acetylation in sexual stage malaria parasites is a target for antimalarial small molecules

Trenholme, Katharine, Marek, Linda, Duffy, Sandra, Pradel, Gabriele, Fisher, Gillian, Hansen, Finn K., Skinner-Adams, Tina S., Butterworth, Alice, Ngwa, Che Julius, Moecking, Jonas, Goodman, Christopher D., McFadden, Geoffrey I., Sumanadasa, Subathdrage D. M., Fairlie, David P., Avery, Vicky M., Kurz, Thomas and Andrews, Katherine T. (2014) Lysine acetylation in sexual stage malaria parasites is a target for antimalarial small molecules. Antimicrobial Agents and Chemotherapy, 58 7: 3666-3678. doi:10.1128/AAC.02721-13

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Author Trenholme, Katharine
Marek, Linda
Duffy, Sandra
Pradel, Gabriele
Fisher, Gillian
Hansen, Finn K.
Skinner-Adams, Tina S.
Butterworth, Alice
Ngwa, Che Julius
Moecking, Jonas
Goodman, Christopher D.
McFadden, Geoffrey I.
Sumanadasa, Subathdrage D. M.
Fairlie, David P.
Avery, Vicky M.
Kurz, Thomas
Andrews, Katherine T.
Title Lysine acetylation in sexual stage malaria parasites is a target for antimalarial small molecules
Journal name Antimicrobial Agents and Chemotherapy   Check publisher's open access policy
ISSN 0066-4804
Publication date 2014
Year available 2014
Sub-type Article (original research)
DOI 10.1128/AAC.02721-13
Open Access Status File (Publisher version)
Volume 58
Issue 7
Start page 3666
End page 3678
Total pages 13
Place of publication Washington, DC, United States
Publisher American Society for Microbiology
Collection year 2015
Language eng
Subject 2736 Pharmacology (medical)
3004 Pharmacology
2725 Infectious Diseases
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. Copyright
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Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Medicine Publications
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 10 times in Thomson Reuters Web of Science Article | Citations
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