Species-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2

Writing and erasing of posttranslational modifications are crucial to phenotypic plasticity and antigenic variation of eukaryotic pathogens. Targeting pathogens’ modification machineries, thus, represents a valid approach to fighting parasitic diseases. However, identification of parasitic targets and the development of selective anti-parasitic drugs still represent major bottlenecks. Here, we show that the zinc-dependent histone deacetylases (HDACs) of the protozoan parasite Trypanosoma cruzi are key regulators that have significantly diverged from their human counterparts. Depletion of T. cruzi class I HDACs tcDAC1 and tcDAC2 compromises cell-cycle progression and division, leading to cell death. Notably, tcDAC2 displays a deacetylase activity essential to the parasite and shows major structural differences with human HDACs. Specifically, tcDAC2 harbors a modular active site with a unique subpocket targeted by inhibitors showing substantial anti-parasitic effects in cellulo and in vivo. Thus, the targeting of the many atypical HDACs in pathogens can enable anti-parasitic selective chemical impairment. [Display omitted] •Trypanosome histone deacetylases (HDACs) significantly diverge from human HDACs•T. cruzi class I HDACs tcDAC1 and tcDAC2 are essential to the parasite viability•tcDAC2 deacetylase activity can be inhibited by targeting its atypical active site•T. cruzi parasites can be targeted through a tcDAC2-specific inhibitor Marek et al. show that histone deacetylases (HDACs) from trypanosomes diverge from human HDACs. Notably, T. cruzi HDACs tcDAC1 and tcDAC2 are essential. tcDAC2 has structural features unobserved in human HDACs that promote specific interactions with inhibitors. Thus, targeting atypical HDACs from pathogens can lead to anti-parasitic strategies.