1,3,4-oxadiazoles as inhibitors of the atypical member of the BET family bromodomain factor 3 from Trypanosoma cruzi (TcBDF3)

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dc.citation.titleFrontiers in Microbiology
dc.citation.volume15
dc.creatorAlonso, Victoria Lucía
dc.creatorEscalante, Andrea Marta
dc.creatorRodríguez Araya, Elvio
dc.creatorFrattini, Gianfranco
dc.creatorTavernelli, Luis Emilio
dc.creatorMoreno, Diego M.
dc.creatorFurlán, Ricardo Luis Eugenio
dc.creatorSerra, Esteban Carlos
dc.date.accessioned2025-02-27T12:22:35Z
dc.date.available2025-02-27T12:22:35Z
dc.date.issued2024-10-01
dc.description.abstractChagas disease, caused by the protozoan parasite Trypanosoma cruzi, 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 TcBDF3, 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 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, which exhibited improved trypanocide activity and cytotoxicity profiles. Furthermore, TcBDF3 was classified for the first time as an atypical divergent member of the bromodomain extraterminal 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.
dc.description.filFil: Alonso, Victoria Lucía. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET); Argentina.
dc.description.filFil: Escalante, Andrea Marta. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Química Orgánica. Área Farmacognosia; Argentina.
dc.description.filFil: Rodríguez Araya, Elvio. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET); Argentina.
dc.description.filFil: Frattini, Gianfranco. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química de Rosario (IQUIR-CONICET); Argentina.
dc.description.filFil: Tavernelli, Luis Emilio. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET); Argentina.
dc.description.filFil: Moreno, Diego M. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Química de Rosario (IQUIR-CONICET); Argentina.
dc.description.filFil: Furlán, Ricardo Luis Eugenio. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Área Farmacognosia; Argentina.
dc.description.filFil: Serra, Esteban Carlos. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario (IBR-CONICET); Argentina.
dc.description.sponsorshipAgencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación (Agencia I+D+i): PICT-2020-SERIEA-01704, PICT2019-0526
dc.description.sponsorshipUniversidad Nacional de Rosario (UNR): 800-201903-00048UR
dc.description.versionpeerreviewed
dc.format.extent1-13
dc.identifier.citationAlonso, V. L., Escalante, A. M., Rodríguez Araya, E., Frattini, G., Tavernelli, L. E., Moreno, D. M., Furlán, R. L. E. and Serra, E. (2024). 1,3,4-oxadiazoles as inhibitors of the atypical member of the BET family bromodomain factor 3 from Trypanosoma cruzi (TcBDF3). Frontiers in Microbiology, 15. https://doi.org/10.3389/fmicb.2024.1465672
dc.identifier.e-issn1664-302X
dc.identifier.urihttps://hdl.handle.net/2133/28960
dc.language.isoen
dc.publisherFrontiers
dc.relation.publisherversionhttps://doi.org/10.3389/fmicb.2024.1465672
dc.relation.publisherversionhttps://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2024.1465672/full
dc.rightsopenAccess
dc.rights.holderAlonso, Victoria Lucía
dc.rights.holderEscalante, Andrea Marta
dc.rights.holderRodríguez Araya, Elvio
dc.rights.holderFrattini, Gianfranco
dc.rights.holderTavernelli, Luis Emilio
dc.rights.holderMoreno, Diego M.
dc.rights.holderFurlán, Ricardo Luis Eugenio
dc.rights.holderSerra, Esteban Carlos
dc.rights.holderUniversidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas
dc.rights.textAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectBromodomain
dc.subjectChagas disease
dc.subjectTubulin acetylation
dc.subjectCytoskeleton
dc.subject1,3,4-oxadiazoles
dc.subjectBET bromodomain
dc.title1,3,4-oxadiazoles as inhibitors of the atypical member of the BET family bromodomain factor 3 from Trypanosoma cruzi (TcBDF3)
dc.typearticulo
dc.type.collectionarticulo
dc.type.versionpublishedVersion

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