1,3,4-oxadiazoles as inhibitors of the atypical member of the BET family bromodomain factor 3 from <i>Trypanosoma cruzi</i> (<i>Tc</i>BDF3).

Abstract

Chagas disease, caused by the protozoan parasite <i>Trypanosoma cruzi</i>, affects millions globally, with increasing urban cases outside of Latin America. Treatment is based on two compounds, namely, benznidazole (BZ) and nifurtimox, but chronic cases pose several challenges. Targeting lysine acetylation, particularly bromodomain-containing proteins, shows promise as a novel antiparasitic target. Our research focuses on <i>Tc</i>BDF3, a cytoplasmic protein, which is crucial for parasite differentiation that recognizes acetylated alpha-tubulin. In our previous study, A1B4 was identified as a high-affinity binder of <i>Tc</i>BDF3, showing significant trypanocidal activity with low host toxicity <i>in vitro</i>. In this report, the binding of <i>Tc</i>BDF3 to A1B4 was validated using differential scanning fluorescence, fluorescence polarization, and molecular modeling, confirming its specific interaction. Additionally, two new 1,3,4-oxadiazoles derived from A1B4 were identified, which exhibited improved trypanocide activity and cytotoxicity profiles. Furthermore, <i>Tc</i>BDF3 was classified for the first time as an atypical divergent member of the bromodomain extraterminal family found in protists and plants. These results make <i>Tc</i>BDF3 a unique target due to its localization and known functions not shared with higher eukaryotes, which holds promise for Chagas disease treatment.