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ORIGINAL RESEARCH article

Front. Microbiol.
Sec. Antimicrobials, Resistance and Chemotherapy
Volume 15 - 2024 | doi: 10.3389/fmicb.2024.1465672
This article is part of the Research Topic Advancing Strategies to Combat Protozoan Diseases: From Drug Resistance to Innovative Treatments View all 3 articles

1,3,4-Oxadiazoles as inhibitors of the atypical member of the BET family Bromodomain Factor 3 from Trypanosoma cruzi (TcBDF3)

Provisionally accepted
Victoria L. Alonso Victoria L. Alonso 1,2Andrea M. Escalante Andrea M. Escalante 2Elvio R. Araya Elvio R. Araya 1,2Gianfranco Frattini Gianfranco Frattini 2,3Luis E. Tavernelli Luis E. Tavernelli 1Diego M. Moreno Diego M. Moreno 2,3Ricardo L. Furlan Ricardo L. Furlan 2Esteban Serra Esteban Serra 1,2*
  • 1 CONICET Instituto de Biología Molecular y Celular de Rosario (IBR), Rosario, Argentina
  • 2 Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Santa Fe, Argentina
  • 3 CONICET Instituto de Química Rosario (IQUIR), Rosario, Buenos Aires, Argentina

The final, formatted version of the article will be published soon.

    Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, affects millions globally with increasing urban cases outside of Latin America. Treatment in based on two drugs: benznidazole 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 TcBDF3, a cytoplasmic protein crucial for parasite differentiation that recognizes acetylated alpha-tubulin. In previous work, A1B4 was identified as a high-affinity binder of TcBDF3, showing significant trypanocidal activity with low host toxicity in vitro. In this report, the binding of TcBDF3 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, that exhibit improved trypanocide activity and cytotoxicity profiles. Furthermore, TcBDF3 was classified for the first time as an atypical divergent member of the Bromodomain Extra-Terminal family found in protists and plants. These results make TcBDF3 a unique target due to its localization and known functions not shared with higher eukaryotes, which holds promise for Chagas disease treatment.

    Keywords: Bromodomain, Chagas Disease, tubulin acetylation, Cytoskeleton, 1,3,4-Oxadiazoles

    Received: 16 Jul 2024; Accepted: 09 Sep 2024.

    Copyright: © 2024 Alonso, Escalante, Araya, Frattini, Tavernelli, Moreno, Furlan and Serra. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Esteban Serra, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, S2002LRK, Santa Fe, Argentina

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