Russell, Catherine, Carter, Jennifer, Borgia, Juliet Marie et al. (7 more authors) (2023) Bromodomain Factor 5 as a Target for Antileishmanial Drug Discovery. ACS Infectious Diseases. ISSN 2373-8227
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 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 polarisation 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 polarisation 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 optimised antileishmanial compounds targeting this epigenetic reader protein.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © 2023 The Authors. |
Dates: |
|
Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Biology (York) The University of York > Faculty of Sciences (York) > Chemistry (York) |
Funding Information: | Funder Grant number BBSRC (BIOTECHNOLOGY AND BIOLOGICAL SCIENCES RESEARCH COUNCIL) BB/T017805/1 |
Depositing User: | Pure (York) |
Date Deposited: | 18 Oct 2023 09:30 |
Last Modified: | 23 Jan 2025 00:33 |
Published Version: | https://doi.org/10.1021/acsinfecdis.3c00431 |
Status: | Published online |
Refereed: | Yes |
Identification Number: | 10.1021/acsinfecdis.3c00431 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:204344 |
Download
Filename: russell_et_al_2023_bromodomain_factor_5_as_a_target_for_antileishmanial_drug_discovery.pdf
Description: Bromodomain Factor 5 as a Target for Antileishmanial Drug Discovery
Licence: CC-BY 2.5