Bromodomain Factor 5 as a Target for Antileishmanial Drug Discovery
Open accessPreprint — published as 10.1021/acsinfecdis.3c00431
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 drug target in Leishmania and provide a foundation for the future development of optimised antileishmanial compounds targeting this epigenetic reader protein.
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Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
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- Authors
- Russell, C. N., Carter, J. L., Borgia, J. M., Bush, J., Calderon, F., Gabarro, R., Conway, S. J., Mottram, J. C., Wilkinson, A. J., & Jones, N. G.
- Affiliations
- University of York (GB)
- University of Oxford (GB)
- Corresponding author
- Jones, Nathaniel Gadsby
- ORCID
- Venue
- ACS Infectious Diseases
- Publisher
- openRxiv
- Published
- 2023-08-21
- Volume
- 9
- Issue
- 11
- Pages
- 2340-2357
- ISSN
- 2373-8227 (ISSN-L)
- PMC
- PMC10644352
- OpenAlex
- W4388040825
- Cited by
- 10
- References
- 1
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 2
- FWCI
- 2.56
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- ACS Infectious Diseases (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- GlaxoSmithKline
- Wellcome Trust (204829)
- St. Hugh's College, University of Oxford
- Diamond Light Source (mx18598, 18598)
- Medical Research Council (MR/P027989/1)
- Engineering and Physical Sciences Research Council (EP/R513295/, EP/R513295/1, BB/M011151/1)
- Biotechnology and Biological Sciences Research Council (BB/M011151, BB/T017805/1, BB/M011151/1)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Research on Leishmaniasis Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Epidemiology › Trypanosoma species research and implications
- Keywords
- Leishmania donovani, antileishmanial drug discovery, bromodomain inhibitors, epigenetic reader protein, histone acetylation, histone H2B, histone H4, Leishmania promastigotes, neglected tropical diseases, epigenetic drug targets
- MeSH terms
- Protein Domains, Bromodomain Containing Proteins, Antiprotozoal Agents, Factor V, Histones, Humans, Transcription Factors, Drug Discovery
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