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 mu M and/or displayed similar to 40-50 % activity in adult worms at 10 mu M, joined to moderate to no toxicity in human fibroblast MRC-5 cells.
Noce, B., Di Bello, E., Zwergel, C., Fioravanti, R., Valente, S., Rotili, D., et al. (2023). Chemically Diverse S. mansoni HDAC8 Inhibitors Reduce Viability in Worm Larval and Adult Stages. CHEMMEDCHEM, 18(3) [10.1002/cmdc.202200510].
Chemically Diverse S. mansoni HDAC8 Inhibitors Reduce Viability in Worm Larval and Adult Stages
Rotili, Dante;
2023-01-01
Abstract
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 mu M and/or displayed similar to 40-50 % activity in adult worms at 10 mu M, joined to moderate to no toxicity in human fibroblast MRC-5 cells.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
