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Plasmodium falciparum histone deacetylase 1

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Target id: 3072

Nomenclature: Plasmodium falciparum histone deacetylase 1

Abbreviated Name: PfHDAC1

Family: Histone deacetylases (HDACs) (Plasmodium spp.)

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Plasmodium falciparum 3D7 - 449 HDAC1 histone deacetylase 1
Previous and Unofficial Names Click here for help
PfKDAC1
Database Links Click here for help
ChEMBL Target
PlasmoDB
UniProtKB
Whole Organism Assay Data Linked to This Target
Key to terms and symbols Click column headers to sort
Ligand Sp. Assay description Type Action Value Parameter Reference
compound 1u [PMID: 30245402] Small molecule or natural product PfDd2 Parasite growth inhibition assay - - 9.0 pIC50 2
pIC50 9.0 (IC50 1x10-9 M) [3H]-hypoxanthine incorporation [2]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
compound 1u [PMID: 30245402] Small molecule or natural product Pf3D7 Parasite growth inhibition assay - - 8.4 pIC50 2
pIC50 8.4 (IC50 4x10-9 M) [3H]-hypoxanthine incorporation [2]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
compound 2h [PMID: 30664827] Small molecule or natural product Pf3D7 Parasite growth inhibition assay - - 8.3 pIC50 6
pIC50 8.3 (IC50 5.2x10-9 M) [3H]-hypoxanthine incorporation [6]
Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont)
compound 1u [PMID: 30245402] Small molecule or natural product Pb Parasite liver stage assay - - 7.6 pIC50 2
pIC50 7.6 (IC50 2.5x10-8 M) P. berghei Luciferase liver stage assay [2]
Lifecycle stages: Plasmodium liver stage (sporozoite, hepatic schizont, hepatic merozoite)
Malaria Pharmacology Comments
The histone deacetylase (HDAC) family of enzymes are involved in the post-translational modification of histones by removal of acetyl groups from lysine residues. Removal of the acetyl groups facilitates tighter packing of chromatin (heterochromatin formation) leading to transcriptional repression. In humans, the 18 members of the HDAC family have been classified in to five subfamilies based on phylogenetic comparison with yeast homologues (see our HDACs Concise family page for more details). A recent review and analysis of the P. falciparum genome confirmed and classified the five known HDACs for this species of the parasite and identified a novel putative HDAC [5]:
Class I contains PfHDAC1
Class II contains PfHDA1 and PfHDA2
Class III contains the sirtuin-like PfSir2A and PfSir2B
PfCHD1 is a novel unclassified HDAC
HDACs have been identified as attractive molecular targets in the search for novel mechanisms to treat cancer and several small molecule HDAC inhibitors are already approved for clinical use. HDAC inhibitors have also emerged as potential therapies in a number of other disesases including malaria [1,3-4].

References

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1. Andrews KT, Tran TN, Lucke AJ, Kahnberg P, Le GT, Boyle GM, Gardiner DL, Skinner-Adams TS, Fairlie DP. (2008) Potent antimalarial activity of histone deacetylase inhibitor analogues. Antimicrob Agents Chemother, 52 (4): 1454-61. [PMID:18212103]

2. Diedrich D, Stenzel K, Hesping E, Antonova-Koch Y, Gebru T, Duffy S, Fisher G, Schöler A, Meister S, Kurz T et al.. (2018) One-pot, multi-component synthesis and structure-activity relationships of peptoid-based histone deacetylase (HDAC) inhibitors targeting malaria parasites. Eur J Med Chem, 158: 801-813. [PMID:30245402]

3. Engel JA, Jones AJ, Avery VM, Sumanadasa SD, Ng SS, Fairlie DP, Skinner-Adams T, Andrews KT. (2015) Profiling the anti-protozoal activity of anti-cancer HDAC inhibitors against Plasmodium and Trypanosoma parasites. Int J Parasitol Drugs Drug Resist, 5 (3): 117-26. [PMID:26199860]

4. Hansen FK, Sumanadasa SD, Stenzel K, Duffy S, Meister S, Marek L, Schmetter R, Kuna K, Hamacher A, Mordmüller B et al.. (2014) Discovery of HDAC inhibitors with potent activity against multiple malaria parasite life cycle stages. Eur J Med Chem, 82: 204-13. [PMID:24904967]

5. Kanyal A, Rawat M, Gurung P, Choubey D, Anamika K, Karmodiya K. (2018) Genome-wide survey and phylogenetic analysis of histone acetyltransferases and histone deacetylases of Plasmodium falciparum. FEBS J, 285 (10): 1767-1782. [PMID:29284196]

6. Mackwitz MKW, Hesping E, Antonova-Koch Y, Diedrich D, Woldearegai TG, Skinner-Adams T, Clarke M, Schöler A, Limbach L, Kurz T et al.. (2019) Structure-Activity and Structure-Toxicity Relationships of Peptoid-Based Histone Deacetylase Inhibitors with Dual-Stage Antiplasmodial Activity. ChemMedChem, 14 (9): 912-926. [PMID:30664827]

How to cite this page

Histone deacetylases (HDACs) (Plasmodium spp.): Plasmodium falciparum histone deacetylase 1. Last modified on 01/02/2021. Accessed on 30/07/2021. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=3072.