Catherine Russell

Investigating Bromodomain Proteins as Targets for anti-Leishmanial Drug Discovery

About me

I am a structural biologist currently undertaking a PhD at the University of York. My PhD project combines structural biology with epigenetics and parasitology in an attempt to better understand a class of protein domains known as bromodomains. I aim to assess whether these epigenetic reader domains can be used as drug targets in the treatment of a parasitic disease known as leishmaniasis.

Prior to starting my PhD I completed an MBiochem integrated master’s degree at the University of York, with my research project concerning structural analysis of inhibitor binding the primase enzyme in E. coli.

I undertook a placement at the University of Sheffield as part of my undergraduate degree where I investigated the mechanisms involved in the pathophysiology of otitis media using a mouse model of the disease.

My project

Leishmaniasis is a parasitic disease highly prevalent in tropical areas associated with poverty. It is classed by the World Health Organisation as a neglected tropical disease and is responsible for tens of thousands of deaths annually. Current treatments for the disease have severe drawbacks and we are in desperate need of new anti-leishmanial drugs.

Within chromatin, DNA is packaged into nucleosomes with proteins known as histones. These histone proteins can undergo post translational modifications such as acetylation which can alter chromatin structure and be recognised by other proteins which influence whether the DNA is transcribed or not. This is known as epigenetic regulation of gene expression. Bromodomains are protein domains found in many organisms which ‘read’ the epigenetic histone acetylation mark. These domains bind to acetylated lysine residues on histones and regulate gene expression through various mechanisms such as recruitment of other proteins to DNA, or acting as parts of larger chromatin remodelling complexes. Bromodomains have also been associated with disease, particularly cancer, which has led to research into inhibitors that target proteins containing these domains. This has been particularly successful in cancer research, with several bromodomain inhibitors entering clinical trials.

The parasite that causes leishmaniasis is Leishmania. This parasite also uses epigenetic regulation and has been found to possess bromodomains. Research suggests these bromodomains have essential roles for the parasite, thus posing promising targets for the treatment of the disease. Using structural biology techniques, I am investigating Leishmania bromodomains to better understand their structure, function and binding mechanisms. I am also investigating inhibitors of the bromodomains, using a variety of biophysical techniques, to identify inhibitors that show promise as precursors for potential new treatments of leishmaniasis.