Phenotypic Screening of Histone Deacetylase (HDAC) Inhibitors against Schistosoma mansoni.
Fiche publication
Date publication
août 2022
Journal
ChemMedChem
Auteurs
Membres identifiés du Cancéropôle Est :
Dr ROMIER Christophe
Tous les auteurs :
Hassan MM, Sedighi A, Olaoye OO, Häberli C, Merz A, Ramos-Morales E, de Araujo ED, Romier C, Jung M, Keiser J, Gunning PT
Lien Pubmed
Résumé
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 IC values against HDAC8<100 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, IC =1.5 μM; MMH259, IC =2.3 μM) and adult S. mansoni (MMH258, IC =2.1 μM; MMH373, IC =3.4 μM). Our results indicate that neither hHDAC8 nor SmHDAC8 activity were directly correlated to their NTS and adult S. mansoni activities.
Mots clés
HDAC inhibitors, HDAC8 selective, Schistosoma mansoni, epigenetic therapy, schistosomiasis
Référence
ChemMedChem. 2022 08 19;:e202100622