Phenotypic Screening of Histone Deacetylase (HDAC) Inhibitors against Schistosoma mansoni.
ChemMedChem
; 17(18): e202100622, 2022 09 16.
Article
em En
| MEDLINE
| ID: mdl-35983937
ABSTRACT
Schistosomiasis is a prevalent yet neglected tropical parasitic disease caused by the Schistosoma genus of blood flukes. Praziquantel is the only currently available treatment, hence drug resistance poses a major threat. Recently, histone deacetylase 8 (HDAC8) selective inhibitors have been proposed as a viable treatment for schistosomiasis. Herein, we report the phenotypic screening of a focused library of small molecules of varying HDAC isozyme-inhibition profiles, including eight HDAC8 inhibitors with >10-fold selectivity in comparable functional inhibition assays and IC50 values against HDAC8<100â
nM. HDAC8-selective inhibitors showed the lowest potency against Schistosoma mansoni newly transformed schistosomula (NTS). Pan-HDAC inhibitors MMH258, MMH259, and MMH373, as assessed by functional inhibition assays, with minimal or no-observed hHDAC8 and SmHDAC8 activities, were active against both NTS (MMH258, IC50 =1.5â
µM; MMH259, IC50 =2.3â
µM) and adult S. mansoni (MMH258, IC50 =2.1â
µM; MMH373, IC50 =3.4â
µM). Our results indicate that neither hHDAC8 nor SmHDAC8 activity were directly correlated to their NTS and adult S. mansoni activities.
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Base de dados:
MEDLINE
Assunto principal:
Esquistossomose
/
Inibidores de Histona Desacetilases
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article