The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugs.
Journal
PLoS neglected tropical diseases
ISSN: 1935-2735
Titre abrégé: PLoS Negl Trop Dis
Pays: United States
ID NLM: 101291488
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
received:
20
07
2020
accepted:
10
02
2021
revised:
15
03
2021
pubmed:
4
3
2021
medline:
25
6
2021
entrez:
3
3
2021
Statut:
epublish
Résumé
Echinococcosis and cysticercosis are neglected tropical diseases caused by cestode parasites (family Taeniidae). Not only there is a small number of approved anthelmintics for the treatment of these cestodiases, but also some of them are not highly effective against larval stages, such that identifying novel drug targets and their associated compounds is critical. Histone deacetylase (HDAC) enzymes are validated drug targets in cancers and other diseases, and have been gaining relevance for developing new potential anti-parasitic treatments in the last years. Here, we present the anthelmintic profile for a panel of recently developed HDAC inhibitors against the model cestode Mesocestoides vogae (syn. M. corti). Phenotypic screening was performed on M. vogae by motility measurements and optical microscopic observations. Some HDAC inhibitors showed potent anthelmintic activities; three of them -entinostat, TH65, and TH92- had pronounced anthelmintic effects, reducing parasite viability by ~100% at concentrations of ≤ 20 μM. These compounds were selected for further characterization and showed anthelmintic effects in the micromolar range and in a time- and dose-dependent manner. Moreover, these compounds induced major alterations on the morphology and ultrastructural features of M. vogae. The potencies of these compounds were higher than albendazole and the anthelmintic effects were irreversible. Additionally, we evaluated pairwise drug combinations of these HDAC inhibitors and albendazole. The results suggested a positive interaction in the anthelmintic effect for individual pairs of compounds. Due to the maximum dose approved for entinostat, adjustments in the dose regime and/or combinations with currently-used anthelmintic drugs are needed, and the selectivity of TH65 and TH92 towards parasite targets should be assessed. The results presented here suggest that HDAC inhibitors represent novel and potent drug candidates against cestodes and pave the way to understanding the roles of HDACs in these parasites.
Sections du résumé
BACKGROUND
Echinococcosis and cysticercosis are neglected tropical diseases caused by cestode parasites (family Taeniidae). Not only there is a small number of approved anthelmintics for the treatment of these cestodiases, but also some of them are not highly effective against larval stages, such that identifying novel drug targets and their associated compounds is critical. Histone deacetylase (HDAC) enzymes are validated drug targets in cancers and other diseases, and have been gaining relevance for developing new potential anti-parasitic treatments in the last years. Here, we present the anthelmintic profile for a panel of recently developed HDAC inhibitors against the model cestode Mesocestoides vogae (syn. M. corti).
METHODOLOGY/PRINCIPAL FINDINGS
Phenotypic screening was performed on M. vogae by motility measurements and optical microscopic observations. Some HDAC inhibitors showed potent anthelmintic activities; three of them -entinostat, TH65, and TH92- had pronounced anthelmintic effects, reducing parasite viability by ~100% at concentrations of ≤ 20 μM. These compounds were selected for further characterization and showed anthelmintic effects in the micromolar range and in a time- and dose-dependent manner. Moreover, these compounds induced major alterations on the morphology and ultrastructural features of M. vogae. The potencies of these compounds were higher than albendazole and the anthelmintic effects were irreversible. Additionally, we evaluated pairwise drug combinations of these HDAC inhibitors and albendazole. The results suggested a positive interaction in the anthelmintic effect for individual pairs of compounds. Due to the maximum dose approved for entinostat, adjustments in the dose regime and/or combinations with currently-used anthelmintic drugs are needed, and the selectivity of TH65 and TH92 towards parasite targets should be assessed.
CONCLUSION, SIGNIFICANCE
The results presented here suggest that HDAC inhibitors represent novel and potent drug candidates against cestodes and pave the way to understanding the roles of HDACs in these parasites.
Identifiants
pubmed: 33657105
doi: 10.1371/journal.pntd.0009226
pii: PNTD-D-20-01305
pmc: PMC7959350
doi:
Substances chimiques
Anthelmintics
0
Benzamides
0
Histone Deacetylase Inhibitors
0
Pyridines
0
entinostat
1ZNY4FKK9H
Albendazole
F4216019LN
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0009226Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
Parasitol Res. 2003 Apr;89(6):467-72
pubmed: 12658458
Neurol Clin. 2018 Nov;36(4):851-864
pubmed: 30366559
ACS Infect Dis. 2020 Jan 10;6(1):100-113
pubmed: 31661956
PLoS Negl Trop Dis. 2009;3(2):e319
pubmed: 19238190
Korean J Parasitol. 2011 Mar;49(1):73-7
pubmed: 21461273
Parasitology. 2019 Apr;146(5):553-562
pubmed: 30430955
PLoS Negl Trop Dis. 2018 Feb 9;12(2):e0006267
pubmed: 29425245
ChemMedChem. 2012 Oct;7(10):1815-24
pubmed: 22907916
Infect Genet Evol. 2017 Sep;53:175-188
pubmed: 28506839
Antimicrob Agents Chemother. 2012 Jul;56(7):3849-56
pubmed: 22508312
Nat Rev Drug Discov. 2012 Apr 13;11(5):384-400
pubmed: 22498752
Bioorg Med Chem. 2008 Feb 15;16(4):2011-33
pubmed: 18054239
Parasitol Res. 1998;84(3):230-8
pubmed: 9521013
Interdiscip Perspect Infect Dis. 2014;2014:268135
pubmed: 25258624
Int J Parasitol Drugs Drug Resist. 2017 Apr;7(1):42-50
pubmed: 28107750
Int J Parasitol. 1982 Aug;12(4):303-14
pubmed: 7118373
Molecules. 2015 Jun 26;20(7):11793-807
pubmed: 26132905
Parasitology. 1997 May;114 ( Pt 5):475-82
pubmed: 9149418
Curr Top Med Chem. 2018;18(5):369-381
pubmed: 29741140
Trends Pharmacol Sci. 2015 Jul;36(7):481-92
pubmed: 26013035
PLoS Pathog. 2013;9(9):e1003645
pubmed: 24086136
Int J Parasitol. 2012;42(3):221-4
pubmed: 22366548
J Med Chem. 2018 Nov 21;61(22):10000-10016
pubmed: 30347148
Curr Top Dev Biol. 2014;108:71-93
pubmed: 24512706
J Med Chem. 2017 Dec 28;60(24):10188-10204
pubmed: 29190092
J Helminthol. 2019 Sep;93(5):640-642
pubmed: 30064529
Acta Trop. 1997 Apr 1;64(1-2):79-93
pubmed: 9095290
J Med Chem. 2016 Feb 25;59(4):1545-55
pubmed: 26653328
Nat Rev Drug Discov. 2019 Jan;18(1):41-58
pubmed: 30310233
Future Oncol. 2017 Jun;13(13):1137-1148
pubmed: 28326839
ChemMedChem. 2020 Apr 3;15(7):571-584
pubmed: 31816172
Anticancer Res. 2004 Mar-Apr;24(2B):539-45
pubmed: 15160991
J Mol Graph Model. 2015 Nov;62:342-361
pubmed: 26595183
Biochem J. 2008 Jan 15;409(2):581-9
pubmed: 17868033
Int J Parasitol Drugs Drug Resist. 2019 Apr;9:120-132
pubmed: 30897528
ChemMedChem. 2018 Aug 10;13(15):1517-1529
pubmed: 29806110
Immunol Cell Biol. 2012 Jan;90(1):66-77
pubmed: 22124373
Parasitol Int. 2006 Mar;55(1):51-61
pubmed: 16325461
World J Gastroenterol. 2017 Dec 7;23(45):7989-7999
pubmed: 29259374
Bioorg Med Chem. 2015 Aug 15;23(16):5151-5
pubmed: 25637120
Molecules. 2018 Feb 02;23(2):
pubmed: 29393896
J Neurosci Methods. 2007 Apr 15;161(2):273-80
pubmed: 17207862
Nature. 2013 Oct 24;502(7472):480-8
pubmed: 24153301
J Parasitol. 1965 Apr;51:268-72
pubmed: 14275221
Parasite. 2014;21:70
pubmed: 25526545
PLoS Pathog. 2012 Feb;8(2):e1002489
pubmed: 22346746
Trends Parasitol. 2015 Sep;31(9):407-12
pubmed: 26115902
J Pharmacol Exp Ther. 2003 Nov;307(2):720-8
pubmed: 12975486
Int J Parasitol Drugs Drug Resist. 2015 Jun 20;5(3):117-26
pubmed: 26199860
Korean J Parasitol. 2011 Sep;49(3):273-5
pubmed: 22072827
J Hematol Oncol. 2015 Jul 10;8:82
pubmed: 26156322
Future Med Chem. 2015;7(6):783-800
pubmed: 25996070
J Parasitol. 2003 Feb;89(1):27-34
pubmed: 12659299
Parasitol Res. 2019 Feb;118(2):687-692
pubmed: 30467616
PLoS Negl Trop Dis. 2014 Jul 17;8(7):e2977
pubmed: 25033456
Front Genet. 2014 Sep 10;5:317
pubmed: 25309576
J Med Chem. 2017 Jun 22;60(12):4780-4804
pubmed: 28241112
J Mol Biol. 2014 Oct 9;426(20):3442-53
pubmed: 24657767
Leukemia. 2008 May;22(5):1026-34
pubmed: 18256683
J Med Chem. 2016 Mar 24;59(6):2423-35
pubmed: 26937828
Blood. 2007 Apr 1;109(7):2781-90
pubmed: 17179232
Curr Pharm Des. 2012;18(24):3567-78
pubmed: 22607147