Bromodomain Factor 5 as a Target for Antileishmanial Drug Discovery

Abstract

Leishmaniases are a collection of neglected tropical diseases caused by kinetoplastid parasites in the genus Leishmania. Current chemotherapies are severely limited, and the need for new antileishmanials is of pressing international importance. Bromodomains are epigenetic reader domains that have shown promising therapeutic potential for cancer therapy and may also present an attractive target to treat parasitic diseases. Here, we investigate Leishmania donovani bromodomain factor 5 (LdBDF5) as a target for antileishmanial drug discovery. LdBDF5 contains a pair of bromodomains (BD5.1 and BD5.2) in an N-terminal tandem repeat. We purified recombinant bromodomains of L. donovani BDF5 and determined the structure of BD5.2 by X-ray crystallography. Using a histone peptide microarray and fluorescence polarization assay, we identified binding interactions of LdBDF5 bromodomains with acetylated peptides derived from histones H2B and H4. In orthogonal biophysical assays including thermal shift assays, fluorescence polarization, and NMR, we showed that BDF5 bromodomains bind to human bromodomain inhibitors SGC–CBP30, bromosporine, and I-BRD9; moreover, SGC–CBP30 exhibited activity against Leishmania promastigotes in cell viability assays. These findings exemplify the potential BDF5 holds as a possible drug target in Leishmania and provide a foundation for the future development of optimized antileishmanial compounds targeting this epigenetic reader protein.

Identification of novel Bromodomain inhibitors ofTrypanosoma cruziBromodomain Factor 2 (TcBDF2) using a fluorescence polarization-base high-throughput assay

“…By contrast, GSK2801 does not bind to Tb BDF3 or the first BD from Tb BDF5 48 . BDF5 from Leishmania donovani was also recently assayed against human BD inhibitors 27 . Ld BDF5 binds to SGC-CBP30, BSP, and I-BRD9, with different affinities for the first or second DB.…”

“…To date, according to the Clinical Trials Database from the National Academy of Medicine, there are 55 studies (either completed or still running) with BD inhibitors mainly targeted to different types of cancer and inflammatory diseases, among others (https://clinicaltrials.gov/, last consultation 12/12/23). In this context, parasitic bromodomains have also been gaining attention as attractive targets to battle NTDs such as American trypanosomiasis, Leishmaniasis, Malaria, and Toxoplasmosis 21–27 .…”