Structural Basis for the Inhibition of Histone Deacetylase 8 (HDAC8), a Key Epigenetic Player in the Blood Fluke Schistosoma mansoni
Figure 6
Designed small-molecule inhibitors show decreased specificity towards human HDACs and induce apoptosis in schistosomes.
(A) IC50 values of SAHA, M344, J1038, J1037, and J1075 for smHDAC8 and human HDAC8, HDAC1, HDAC3, HDAC6 are plotted in graph. J1038 and J1075 show loss of specificities for human HDACs but not for smHDAC8. The results of three independent assays are shown, error bars represent the SD. (B,C) Merged TUNEL (pink) and DAPI (blue) staining of S. mansoni schistosomula incubated with DMSO alone (B) or with 100 µM J1075 dissolved in DMSO (C) for 96 h. (D) Quantification of TUNEL positivity of schistosomula incubated for 96 h with J1075 at 50 µM or 100 µM or with DMSO alone. The results of three independent assays are shown, error bars represent the SD. (E) Dose- and time-dependent mortality of schistosomula induced by J1075 inhibitor. Schistosoma mansoni schistosomula (1000 per well) were incubated in 1 mL of culture medium with varying quantities of J1075 inhibitor or the solvent (DMSO). The results of three independent assays are shown; error bars represent the SD. (F) J1075-triggered separation of S. mansoni adult worm pairs in culture. The paired status of male and female adult worms was assessed daily in the presence of varying quantities of J1075 or the solvent (DMSO). The results of three independent assays are shown, error bars represent the SD.