Artículo
1,3,4-oxadiazoles as inhibitors of the atypical member of the BET family bromodomain factor 3 from Trypanosoma cruzi (TcBDF3)
Alonso, Victoria Lucia
; Escalante, Andrea Marta
; Rodríguez Araya, Elvio
; Frattini, Gianfranco
; Tavernelli, Luis Emilio
; Moreno, Diego Martin
; Furlan, Ricardo Luis Eugenio
; Serra, Esteban Carlos
Fecha de publicación:
10/2024
Editorial:
Frontiers Media
Revista:
Frontiers in Microbiology
ISSN:
1664-302X
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
Chagas 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.
Palabras clave:
1,3,4-OXADIAZOLES
,
INHIBIDORES
,
BROMODOMINIO3
,
TRYPANOSOMA CRUZI
Archivos asociados
Licencia
Identificadores
Colecciones
Articulos(CCT - ROSARIO)
Articulos de CTRO.CIENTIFICO TECNOL.CONICET - ROSARIO
Articulos de CTRO.CIENTIFICO TECNOL.CONICET - ROSARIO
Articulos(IBR)
Articulos de INST.DE BIOLOGIA MOLECULAR Y CELULAR DE ROSARIO
Articulos de INST.DE BIOLOGIA MOLECULAR Y CELULAR DE ROSARIO
Articulos(IQUIR)
Articulos de INST.DE QUIMICA ROSARIO
Articulos de INST.DE QUIMICA ROSARIO
Citación
Alonso, Victoria Lucia; Escalante, Andrea Marta; Rodríguez Araya, Elvio; Frattini, Gianfranco; Tavernelli, Luis Emilio; et al.; 1,3,4-oxadiazoles as inhibitors of the atypical member of the BET family bromodomain factor 3 from Trypanosoma cruzi (TcBDF3); Frontiers Media; Frontiers in Microbiology; 15; 10-2024; 1-13
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