Essential Bromodomain TcBDF2 as a Drug Target against Chagas Disease

• Published in: ACS infectious diseases 2022-05, Vol.8 (5), p.1062-1074
• Main Authors: Pezza, Alejandro, Tavernelli, Luis E., Alonso, Victoria L., Perdomo, Virginia, Gabarro, Raquel, Prinjha, Rab, Rodríguez Araya, Elvio, Rioja, Inmaculada, Docampo, Roberto, Calderón, Felix, Martin, Julio, Serra, Esteban
• Format: Article
• Language: English
• ISSN: 2373-8227; 2373-8227
• DOI: 10.1021/acsinfecdis.2c00057

Trypanosoma cruzi is a unicellular parasite that causes Chagas disease, which is endemic in the American continent but also worldwide, distributed by migratory movements. A striking feature of trypano­somatids is the poly­cistronic transcription associated with post-transcriptional mechanisms that regulate the levels of translatable mRNA. In this context, epigenetic regulatory mechanisms have been revealed to be of great importance, since they are the only ones that would control the access of RNA polymerases to chromatin. Bromo­domains are epigenetic protein readers that recognize and specifically bind to acetylated lysine residues, mostly at histone proteins. There are seven coding sequences for BD-containing proteins in trypano­somatids, named TcBDF1 to TcBDF7, and a putative new protein containing a bromo­domain was recently described. Using the Tet-regulated overexpression plasmid pTcINDEX-GW and CRISPR/Cas9 genome editing, we were able to demonstrate the essentiality of TcBDF2 in T. cruzi. This bromo­domain is located in the nucleus, through a bipartite nuclear localization signal. TcBDF2 was shown to be important for host cell invasion, amastigote replication, and differentiation from amastigotes to trypo­mastigotes. Overexpression of TcBDF2 diminished epimastigote replication. Also, some processes involved in patho­genesis were altered in these parasites, such as infection of mammalian cells, replication of amastigotes, and the number of trypo­mastigotes released from host cells. In in vitro studies, TcBDF2 was also able to bind inhibitors showing a specificity profile different from that of the previously characterized TcBDF3. These results point to TcBDF2 as a druggable target against T. cruzi.