Bromodomain Factor 5 as a Target for Antileishmanial Drug Discovery

TY - JOUR

T1 - Bromodomain Factor 5 as a Target for Antileishmanial Drug Discovery

AU - Russell, Catherine

AU - Carter, Jennifer

AU - Borgia, Juliet Marie

AU - Bush, Jacob

AU - Calderón, Félix

AU - Gabarró, Raquel

AU - Conway, Stuart

AU - Mottram, Jeremy Charles

AU - Wilkinson, Anthony J

AU - Jones, Nathaniel

N1 - © 2023 The Authors.

PY - 2023/10/31

Y1 - 2023/10/31

N2 - 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.

AB - 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.

U2 - 10.1021/acsinfecdis.3c00431

DO - 10.1021/acsinfecdis.3c00431

M3 - Article

SN - 2373-8227

JO - ACS Infectious Diseases

JF - ACS Infectious Diseases

ER -