Background
Epigenetics: some generalities
Histone post-translational modifications
DNA modifications
Epigenetic regulation in the malaria parasite
Epigenetic marks in Plasmodium
Histone post-translational modifications (HPTMs) in Plasmodium
DNA modifications in Plasmodium
Epigenetic effectors in Plasmodium
Histone acetyltransferases/histone deacetylases
Name | PlasmoDB ID | Inferred/Known activity |
---|---|---|
Histone acetyltransferases (HATs) | ||
PfGCN5 [72] | PF3D7_0823300 | H3K9, H3K14 acetylation |
PfMYST [75] | PF3D7_1118600 | H4K5, K8, K12, K16 acetylation |
PfHAT1 [71] | PF3D7_0416400 | Unknown |
PfELP3 [71] | PF3D7_1227800 | Unknown |
Histone deacetylases (HDACs) | ||
PfHDAC1 (Class I) [81] | PF3D7_0925700 | Parasite’s progression through intraerythrocytic developmental cycle |
PfHDA2 (Class II) [45] | PF3D7_1008000 | H3K9 deacetylation involved in gametocyte commitment, virulence gene silencer |
PfHDA1 (Class II) [82] | PF3D7_1472200 | Putative HDAC |
PF3D7_1328800 | Telomere maintenance and var gene silencing | |
PF3D7_1451400 | Silencing of var genes | |
PfSET1 | PF3D7_0629700 | H3K4 methylation |
PfSET2 | PF3D7_1322100 | H3K36 methylation |
PfSET3 | PF3D7_0827800 | H3K9 methylation |
PfSET4 | PF3D7_0910000 | H3K36 methylation |
PfSET5 | PF3D7_1214200 | Unknown |
PfSET6 | PF3D7_1355300 | H3K36 methylation |
PfSET7 | PF3D7_1115200 | H3K36, H3K9, H3K4 methylation |
PfSET8 | PF3D7_0403900 | H4K20 methylation |
PfSET9 | PF3D7_0508100 | H3K36 methylation |
PfSET10 | PF3D7_1221000 | H3K4 methylation |
PfPRMT1 | PF3D7_1426200 | H4R3 methylation |
LSD1 family | ||
PfLSD1 | PF3D7_1211600 | H3K4me1 and me2 demethylation |
PfLSD2 | PF3D7_0801900 | H3K4me1 and me2 demethylation |
Jumonji-related family | ||
PfJmjC1 | PF3D7_0809900 | Histone Lysine Demethylase |
PfJmjC2 | PF3D7_0602800 | Histone Lysine Demethylase |
PfJmjC3 | PF3D7_1122200 | Histone Lysine Demethylase |
PfDNMT2 | PF3D7_0727300 | DNA and tRNA methylation |
Histone methyltransferases / histone demethylases
DNA methyltransferases
Plasmodium epigenetic effectors as a source of therapeutic targets
Case of parasite resistance to anti-malarials
Targeting histone modification
Targeting histone acetyltransferases/histone deacetylases
Inhibitors | Structure | P. falciparum IC50 in µM | Specificity | CC50 on mammalian cells in µM (Cell type) |
---|---|---|---|---|
Anacardic Acid | 30 [115] | Targets lipoxygenase activity [116] | > 100 (HeLa) [145] | |
Curcumin | 25 [97] | No specificity, targets all HATs and involved in production of ROS [97] | 4 (HL60) [146] | |
Embelin | 10 [73] | Specific towards GCN5 | > 40 (mammalian) [73] | |
CB3717 | 0.225; 1 [117] | Specific towards PfGCN5 | > 20 (NIH3T3) [117] | |
NU9056 | 0.9 [118] | Specific towards PfMyst | - |
Targeting Class I and II HDACs | |||||
---|---|---|---|---|---|
Inhibitors | Structure | P. falciparum IC50 in µM | Specificity | Development stage | CC50 on mammalian cells in µM (Cell type) |
Cyclic tetrapeptides | |||||
Apicidin | Targets class I and II HDACs [76] | – | 10 (Jurkat) [148] | ||
CTP-NPDG 19 | 0.3 [122] | Targets class I HDACs | – | > 25 (HepG2) [122] | |
Romidepsin | 0.09 [149] | Targets class I and II HDACs | FDA-approved in cancer therapy | 0.001 (NFF) [149] | |
HC-toxin | < 0.01 [49] | Targets class I and II HDACs | – | 0.9 (TFK-1) [150] | |
FR235222 | 0.01 [151] | Targets class I HDACs | – | 0.13 (HFF) [152] | |
Hydroxamates | |||||
Trichostatin A | Targets class I and II HDACs | – | 0.2 (HeLa) [153] | ||
SAHA (Vorinostat) | Targets class I and II HDACs | FDA-approved in cancer therapy | 5.5 (NFF) [149] | ||
JAHA | 0.5 [147] | Targets class I and II HDACs[154] | – | 2.4 (MCF7) [154] | |
SBHA | 1 [120] | Targets class I and II HDACs | – | 12 (HEK) [155] | |
WR301801 | 0.001 [156] | Targets class I and II HDACs | Tested in vivo | 0.6 (RAW) [156] | |
Belinostat | 0.06 [149] | Targets class I and II HDACs | FDA-approved in cancer therapy | 2.37 (NFF) [149] | |
Panobinostat | 0.01 [149] | Targets class I and II HDACs | FDA-approved in cancer therapy | 0.07 (NFF) [149] | |
FNDR-20123 | 0.04 [124] | Targets class I HDACs | – | > 100 (HepG2 & THP-1) [124] | |
JX21108 | 0.004 [125] | Targets class I HDACs | – | > 4 (HepG2) [125] | |
Compound 29 | 0.45 [139] | Targets class I HDACs | – | 17 (Hela) [139] | |
Peptoid-based hydroxamic acids 2h | 0.005 [138] | HDACs | – | 4.6 (HepG2) [138] | |
2-aminosuberic acid derivatives | |||||
2-aminosuberic acid derivatives | 0.01; 0.3 [120] | Targets class I HDACs | – | 0.2–5.8 (NFF) [120] | |
L-cysteine derivatives | |||||
L-cysteine derivatives | 0.05; 0.34 [120] | Targets class I HDACs | – | 0.35–2.2 (NFF) [120] | |
Targeting Sir2 HDAC (Class III) | |||||
Surfactin | 9.3 [79] | Unknown off-targets since it induces apoptosis | – | 9.6 (MCF-7) [157] | |
Sirtinol | 10 [120] | No off-targets known Inhibits both PfSir2A and B | – | > 25 (NFF) [120] |
Targeting histone methyltransferases/histone demethylases
Inhibitors | Structure | P. falciparum IC50 in µM | Specificity | Development stage | CC50 on mammalian cells in µM (Cell type) |
---|---|---|---|---|---|
UNC0638 | 0.028 [130] | Targets G9a methyltransferases in mammalian cells | – | 23 (HL-60) [158] | |
BIX-01294 | No target properly identified but inhibits H3K4me3 | Tested on a humanized mouse model | 6.1 (HFF) [127] | ||
TM2-115 | Identical to BIX-01294 | Tested on a humanized mouse model | 5.7 (HFF) [127] | ||
Chaetocin | No target properly identified but inhibits H3K9me2/me3 | – | 0.13 (HL-60) [158] |
Inhibitors | Structure | P. falciparum IC50 in µM | Specificity | Development stage | CC50 on mammalian cells in µM (Cell type) |
---|---|---|---|---|---|
Tranylcypromine | > 10 [160] | Inhibits human LSD1 [161] | FDA-approved monoamine oxidase inhibitor | > 200 (HEK293) [162] | |
GSK-J1 | > 10 [130] | Inhibits human Jumonji demethylases | – | 9 (Human primary macrophages) [163] | |
IOX 1 | 1; 10 [160] | Inhibits human Jumonji demethylases [164] | – | 86.5 (HeLa) [164] | |
JIB-04 | – | > 10 (Human mesenchymal stem) [166] |
Targeting DNA modifications
Inhibitors | Structure | P. falciparum IC50 in µM | Specificity | Development stage | CC50 on mammalian cells in µM (Cell type) |
---|---|---|---|---|---|
5-azacytidine | 1.5.103 [51] | Human DNMT [167] | FDA-approved in cancer therapy [167] | 2.3 (KG-1a acute myeloid leukemia)[168] | |
Decitabine | 8.102 [51] | Human DNMT[167] | FDA-approved in cancer therapy [167] | 0.4 (KG-1a acute myeloid leukemia) [168] | |
SGI-1027 | Human DNMT 1, 3A, 3B [169] | - | > 50 (H4IIE rat hepatoma) [169] | ||
Quinoline-quinazoline derivative | 0.06 [132] | PfDNMT | Tested in standard chemosensitivity assays on ART-resistant strains | 2.5 (HepG2) [132] | |
Quinazoline derivative | 0.019 [131] | PfDNMT3 | Tested in standard chemosensitivity assays on multidrug resistant strains | > 1 (Splenic) [131] |