Developments in drug design strategies for bromodomain protein inhibitors to target Plasmodium falciparum parasites

ABSTRACT

Introduction: Bromodomains (BRDs) bind to acetylated lysine residues, often on histones. The BRD proteins can contribute to gene regulation either directly through enzymatic activity or indirectly through recruitment of chromatin-modifying complexes or transcription factors. There is no evidence of direct orthologues of the Plasmodium falciparum BRD proteins (PfBDPs) outside the apicomplexans. PfBDPs are expressed during the parasite’s life cycle in both the human host’s blood and in the mosquito. PfBDPs could also prove to be promising targets for novel antimalarials, which are urgently required to address increasing drug resistance.

Areas covered: This review discusses recent studies of the biology of PfBDPs, current target-based strategies for PfBDP inhibitor discovery, and different approaches to the important step of validating the specificity of hit compounds for PfBDPs.

Expert opinion: The novelty of Plasmodium BRDs suggests that they could be targeted by selective compounds. Chemical series that showed promise in screens against human BRDs could be leveraged to create targeted compound libraries, as could hits from P. falciparum phenotypic screens. These targeted libraries and hits could be screened in target-based strategies aimed at discovery and optimization of novel inhibitors of PfBDPs. A key task for the field is to generate parasite assays to validate the hit compounds’ specificity for PfBDPs.

KEYWORDS:

• Acetylation
• Apicomplexa
• bromodomain
• histones
• epigenetics
• malaria
• Plasmodium falciparum
• target-based drug discovery

Article highlights

• Bromodomain proteins bind to acetylated lysines on histones and directly or indirectly regulate gene transcription.

• A large number of inhibitors of human bromodomains have been discovered.

• P. falciparum has eight bromodomain proteins, seven are unique to apicomplexans, four are probably essential and thus could provide useful targets for much-needed antimalarial drugs.

• Phenotypic screens have generated many hit anti-malarial compounds which together with the existing human BRD binding compounds, could provide a good starting point for screening for P. falciparum BRD inhibitors.

• Recombinant P. falciparum BRDs can be used to develop high-throughput BRD inhibitor screens.

• Specificity of P. falciparum BRD inhibitor hits can be partially validated by sequencing of parasites selected for resistance but there is an urgent need to also develop transgenic parasite assays for hit compound validation.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

M Duffy is funded by the National Health and Medical Research Council of Australia via grant [APP1128975].