Project: Investigating novel chromatin proteins of the malaria parasite P. falciparum as drug targets.
Plasmodium falciparum has novel bromodomain proteins that are involved in creating chromatin structure and gene regulation. We will characterise these proteins as potential drug targets.
The malaria parasite Plasmodium falciparum caused the deaths of approximately 435,000 people in 2017, most of whom were children. P. falciparum multiplies inside our red blood cells and bursts out every 48 hours and then rapidly re-invades fresh red blood cells. Resistance is emerging to our best anti-malarial drugs so new drugs are urgently needed. A promising strategy is to target proteins that are found in P. falciparum but not humans. P. falciparum employs novel chromatin proteins to regulate gene expression in its pared back genome.
Bromodomain proteins (BDPs) bind to acetylated lysine residues on histones within nucleosomes and then can either recruit complexes that further modify chromatin, or recruit transcription factors that directly regulate transcription. Bromodomain inhibitors have shown promise in treating cancer. P. falciparum has 8 novel BDPs, we recently showed that one was an essential regulator of genes required for parasite invasion of erythrocytes (Josling A et al Cell Host Microbe 2015). We have now made recombinant parasites that can be induced to knockout and/or knockdown BDPs. From these parasites three more BDPs are essential whilst two are not required for blood stage survival. All of these BDPs will be assessed for their role in regulating parasite gene expression by RNAseq, their genomic location by ChIPseq, and their functional role in parasites by assessing parasite growth and various parasite phenotypes, e.g. erythrocyte invasion and transition to sexual, transmissible forms. BDPs that have essential, functional roles could be promising, novel drug targets.