Chemically Diverse S. mansoni HDAC8 Inhibitors Reduce Viability in Worm Larval and Adult Stages

Beatrice Noce , Elisabetta Di Bello , Clemens Zwergel , Rossella Fioravanti , Sergio Valente , Dante Rotili , Andrea Masotti , Mohammad Salik Zeya Ansari , Daniela Trisciuoglio , Alokta Chakrabarti , Christophe Romier (1, 2) , Dina Robaa , Wolfgang Sippl , Manfred Jung , Cécile Häberli , Jennifer Keiser , Antonello Mai

1 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
2 IGBMC - Institut de génétique et biologie moléculaire et cellulaire

Schistosoma mansoni HDAC8 is a reliable target to fight schistosomiasis, and several inhibitors have been reported in the literature up to now. Nevertheless, only a few displayed selectivity over the human deacetylases and some exhibited very low or no activity against parasite larvae and/or adult worms. We report here the in vitro enzyme and biological activity of a small library of HDAC inhibitors from our lab, in many cases exhibiting submicromolar/nanomolar potency against smHDAC8 and diverse degrees of selectivity over hHDAC1 and/or hHDAC6. Such compounds were tested against schistosomula, and a selection of them against the adult forms of S. mansoni, to detect their effect on viability. Some of them showed the highest viability reduction for the larval stage with IC50 values around 1 μM and/or displayed ∼40-50 % activity in adult worms at 10 μM, joined to moderate to no toxicity in human fibroblast MRC-5 cells.

Domaines: Biochimie, Biologie Moléculaire

Beatrice Noce, Elisabetta Di Bello, Clemens Zwergel, Rossella Fioravanti, Sergio Valente, et al.. Chemically Diverse S. mansoni HDAC8 Inhibitors Reduce Viability in Worm Larval and Adult Stages. ChemMedChem, 2023, 18 (3), ⟨10.1002/cmdc.202200510⟩. ⟨hal-04219183⟩