Species-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2.
Cell Rep
; 37(12): 110129, 2021 12 21.
Article
in En
| MEDLINE
| ID: mdl-34936867
ABSTRACT
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Trypanosoma cruzi
/
Histone Deacetylase Inhibitors
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Histone Deacetylases
Limits:
Animals
/
Female
/
Humans
/
Male
Language:
En
Journal:
Cell Rep
Year:
2021
Document type:
Article
Affiliation country: