Aim for the Readers! Bromodomains As New Targets Against Chagas’ Disease

Abstract

Bromodomains recognize and bind acetyl-lysine residues present in histone and non-histone proteins in a specific manner. In the last decade they have raised as attractive targets for drug discovery because the miss-regulation of human bromodomains was discovered to be involved in the development of a large spectrum of diseases. However, targeting eukaryotic pathogens bromodomains continues to be almost unexplored. We and others have reported the essentiality of diverse bromodomain- containing proteins in protozoa, offering a new opportunity for the development of antiparasitic drugs, especially for Trypansoma cruzi, the causative agent of Chagas’ disease. Mammalian bromodomains were classified in eight groups based on sequence similarity but parasitic bromodomains are very divergent proteins and are hard to assign them to any of these groups, suggesting that selective inhibitors can be obtained. In this review, we describe the importance of lysine acetylation and bromodomains in T. cruzi as well as the current knowledge on mammalian bromodomains. Also, we summarize the myriad of small-molecules under study to treat different pathologies and which of them have been tested in trypanosomatids and other protozoa. All the information available led us to propose that T. cruzi bromodomains should be considered as important potential targets and the search for smallmolecules to inhibit them should be empowered.

1H, 13C and 15N resonance assignments of TbBDF5-bromo1 domain from Trypanosoma brucei

“…The bromo domain is evolutionarily conserved, consists of about 110 amino acids and shares a globular fold that comprises a left-handed bundle of four α-helices linked by two variable-loop regions, which is conserved across all bromo domains (Filippakopoulos et al 2012). A number of evidences have demonstrated that bromodomain-containing protein can be used as targets for the treatment of cancer and other diseases (Alonso et al 2019;Schulz et al 2015).…”

“…1. Except three non-proline residues (Ser2, Gly68 and Thr75), 1 H and 15 N backbone chemical shifts were assigned for almost all residues (97%). In addition, 95% of NH and 15 N, 97% of 13 C, and 90% of 1 The consensus chemical shift index (CSI), obtained from 1 Hα, 13 Cα and 13 Cβ chemical shifts (values of 1, 0, -1 indicate β-sheet, random coil and α-helical structure, respectively)…”

Protein acetylation in the critical biological processes in protozoan parasites

“…The first indication that inhibiting acetylation modifiers could have antiprotozoal activity occurred in 1996 when Darkin-Rattray et al found that apicidin, a fungal metabolite, was cytotoxic to several protozoan species by disrupting histone acetylation [84]. Since then, inhibitors of KATs, KDACs, and more recently, BDPs have been investigated for their potential as antiprotozoan therapeutic targets [85,86].…”

Essential bromodomain TcBDF2 as a drug target against Chagas disease

“…The BDs from TriTryp BDFs share limited identity among them as well as with any other eukaryotic or bacterial BDs 31 . The inner core is different in each domain and only a limited number of the hyper conserved amino acids are present, also the hydrophobic pocket is mostly constituted by non-identical amino acids with conserved hydrophobicity.…”