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

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 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.

Metalloenzyme Inhibitors against Zoonotic Infections: Focus on Leishmania and Schistosoma

“…Of note, compounds 19 and 20, displayed high potency against newly transformed schistosomula (NTS) (IC 50 values of 1.23 and 1.29 μM, respectively), >50% activity against S. mansoni adult worms at 10 μM, and low toxicity in human retinal pigment epithelium ARPE-19 cells. 54 The sub-micromolar/nanomolar activity of a library of HDAC inhibitors (21−23) against SmHDAC8 has been also reported by Noce et al 55 These hydroxamic acids, displaying different degrees of selectivity over hHDAC1 and/or hHDAC6, were tested against schistosomula showing variable inhibitory activity, exhibiting the highest viability reduction for the larval stage with IC 50 values around 1 μM. Some selected compounds were also tested against S. mansoni adult worms with the most interesting derivatives exhibiting ∼40−50% activity at 10 μM.…”

“…Some selected compounds were also tested against S. mansoni adult worms with the most interesting derivatives exhibiting ∼40−50% activity at 10 μM. 55 Among the non-hydroxamic acid inhibitors, a benzothiadiazine dioxide derivative was identified using a virtual screening approach, based on the development of a structure-based perresidue 3D QSAR (COMBINEr 2.0) model able to rationalize the crucial SmHDAC8−ligand interactions It displayed moderate in vitro inhibitory activity (37% inhibition at 30 μM) against SmHDAC8. To further elucidate the structure− activity relationships of the identified hit, two analogues were synthesized and biologically evaluated, suggesting that the benzothiadiazine dioxide scaffold is able to address the required interactions necessary for SmHDAC8 selectivity.…”

“…The sub-micromolar/nanomolar activity of a library of HDAC inhibitors ( 21 – 23 ) against Sm HDAC8 has been also reported by Noce et al These hydroxamic acids, displaying different degrees of selectivity over hHDAC1 and/or hHDAC6, were tested against schistosomula showing variable inhibitory activity, exhibiting the highest viability reduction for the larval stage with IC 50 values around 1 μM. Some selected compounds were also tested against S. mansoni adult worms with the most interesting derivatives exhibiting ∼40–50% activity at 10 μM …”

Chemical inhibition of bromodomain proteins in insect stage African trypanosomes perturbs silencing of the Variant Surface Glycoprotein repertoire and results in widespread changes in the transcriptome

“…In parasites, bromodomain inhibitors have been shown to bind to bromodomain proteins in T. brucei, T. cruzi, P. falciparum, and L. dovani 23,27,[41][42][43][44] . Inhibition of bromodomain proteins in parasites has been shown to affect differentiation processes in multiple parasite systems 23,45,46 , and therapeutic strategies targeting chromatin interacting proteins have also been proposed and/or demonstrated for trypanosomiasis 23,30 , Chagas disease [47][48][49] , schistosomiasis 50,51 , toxoplasmosis 52,53 , leishmaniasis 54 , and malaria 55,56 .…”

Chemical Inhibition of Bromodomain Proteins in Insect-Stage African Trypanosomes Perturbs Silencing of the Variant Surface Glycoprotein Repertoire and Results in Widespread Changes in the Transcriptome

“…In parasites, bromodomain inhibitors have been shown to bind to bromodomain proteins in T. brucei , Trypanosoma cruzi , Plasmodium falciparum , and Leishmania donovani ( 23 , 27 , 41 – 44 ). Inhibition of bromodomain proteins in parasites has been shown to affect differentiation processes in multiple parasite systems ( 23 , 45 , 46 ), and therapeutic strategies targeting chromatin interacting proteins have also been proposed and/or demonstrated for trypanosomiasis ( 23 , 30 ), Chagas disease ( 47 – 49 ), schistosomiasis ( 50 , 51 ), toxoplasmosis ( 52 , 53 ), leishmaniasis ( 54 ), and malaria ( 55 , 56 ).…”