Potent antimalarial activity of histone deacetylase inhibitor analogues

Andrews, K. T., Tran, T. N., Lucke, A. J., Kahnberg, P., Le, G. T., Boyle, G. M., Gardiner, D. L., Skinner-Adams, T. S. and Fairlie, D. P. (2008) Potent antimalarial activity of histone deacetylase inhibitor analogues. Antimicrobial agents and chemotherapy, 52 4: 1454-1461. doi:10.1128/AAC.00757-07

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Author Andrews, K. T.
Tran, T. N.
Lucke, A. J.
Kahnberg, P.
Le, G. T.
Boyle, G. M.
Gardiner, D. L.
Skinner-Adams, T. S.
Fairlie, D. P.
Title Potent antimalarial activity of histone deacetylase inhibitor analogues
Journal name Antimicrobial agents and chemotherapy   Check publisher's open access policy
ISSN 0066-4804
Publication date 2008-04-01
Year available 2008
Sub-type Article (original research)
DOI 10.1128/AAC.00757-07
Open Access Status File (Publisher version)
Volume 52
Issue 4
Start page 1454
End page 1461
Total pages 8
Editor G.M. Eliopoulos
Place of publication Washington, DC, United States
Publisher American Society for Microbiology
Language eng
Subject C1
970106 Expanding Knowledge in the Biological Sciences
970111 Expanding Knowledge in the Medical and Health Sciences
110803 Medical Parasitology
Abstract The malaria parasite Plasmodium falciparum has at least five putative histone deacetylase (HDAC) enzymes, which have been proposed as new antimalarial drug targets and may play roles in regulating gene transcription, like the better-known and more intensively studied human HDACs (hHDACs). Fourteen new compounds derived from L-cysteine or 2-aminosuberic acid were designed to inhibit P. falciparum HDAC-1 (PfHDAC-1) based on homology modeling with human class I and class II HDAC enzymes. The compounds displayed highly potent antiproliferative activity against drug-resistant (Dd2) or drug sensitive (3D7) strains of P. falciparum in vitro (50% inhibitory concentration of 13 to 334 nM). Unlike known hHDAC inhibitors, some of these new compounds were significantly more toxic to P. falciparum parasites than to mammalian cells. The compounds inhibited P. falciparum growth in erythrocytes at both the early and late stages of the parasite's life cycle and caused altered histone acetylation patterns (hyperacetylation), which is a marker of HDAC inhibition in mammalian cells. These results support PfHDAC enzymes as being promising targets for new antimalarial drugs.
Keyword Microbiology
Pharmacology & Pharmacy
Pharmacology & Pharmacy
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2009 Higher Education Research Data Collection
School of Medicine Publications
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Citation counts: TR Web of Science Citation Count  Cited 73 times in Thomson Reuters Web of Science Article | Citations
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Created: Sat, 18 Apr 2009, 01:44:56 EST by Amanda Jones on behalf of Royal Brisbane Clinical School