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

• Authors: MAREK Martin; RAMOS-MORALES E.; PICCHI-CONSTANTE G.F.A.; BAYER T.; NORSTROM C.; HERP D.; SALES P.A.; GUERRA-SLOMPO E.P.; HAUSMANN K.; CHAKRABARTI A.; SHAIK T.B.; MERZ A.; TROESCH E.; SCHMIDTKUNZ K.; GOLDENBERG S.; PIERCE R.J.; MOURAO MM; JUNG M.M.; SCHULTZ J.; SIPPL W.; ZANCHIN N.I.T.; ROMIER C.
• Year of publication: 2021
• Type: Article in Periodical
• Magazine / Source: Cell Reports
• MU Faculty or unit: Faculty of Science
• Web: https://www.sciencedirect.com/science/article/pii/S2211124721016259?via%3Dihub
• Doi: http://dx.doi.org/10.1016/j.celrep.2021.110129
• Keywords: LYSINE ACETYLATION; HDAC INHIBITORS; IN-VITRO; PARASITES; POTENT; EPIGENETICS; EXPRESSION; MECHANISM; INSIGHTS; FEATURES
• Description: 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 his tone 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.