The Conway Group’s research interests are at the interface of chemistry and biology, and focus on the use of synthetic organic chemistry to develop molecular tools to enable the study of biological systems. Our research can be grouped into three main areas, (1) investigation of the role of epigenetics in health and disease; (2) development of probes to measure and target cellular redox; and (3) identification of molecular tools to study infectious diseases.
Investigation of epigenetic changes in health and disease
Epigenetics is the study of how gene expression is changed and controlled without change to the DNA sequence. Epigenetic modifications occur regularly and are essential for fundamental biological processes such as cell differentiation to form different tissues like skin, brain, or heart. However, changes in the epigenome can also lead to undesired effects and cause of diseases, including cancer.
Modifications to a family of proteins called histones is an area of intense interest in epigenetics. These proteins form a scaffold around which DNA is stored in chromosomes; changes to these proteins influence the structure of chromatin, affecting gene expression. Lysine residues, both in histones and in many other proteins, can be methylated or acetylated post-translationally by enzymes known as ‘writers’; proteins known as ‘erasers’ reverse these processes. Some proteins have a structural motif known as a bromodomain, a protein module of around 110 amino acids, which can recognise or ‘read’ acetylated lysines, helping to modulate the formation of transcriptional complexes, giving them a key role in gene regulation.
We are developing chemical probes that target epigenetic proteins, including those with bromodomains. Using these chemical tools, we have explored their biological function and phenotypical consequences of chemical intervention, helping to develop novel therapeutic strategies for diseases, including cancer.
Novel probes to measure and target cellular redox
In collaboration with Professor Ester Hammond, Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford.
The cellular environment within a living system spans a spectrum between reducing and oxidising conditions. Reducing conditions are characterised by lack of oxygen and chemicals which contain hydrogen. Oxidising conditions are described by the presence of oxygen and reactive oxygen-containing species. The reducing and oxidising species in a cellular environment are responsible for the overall redox state. Redox species are involved in multiple cellular processes including cell signalling and metabolism. The redox equilibrium is important for normal cell function. Consequently, perturbation of the redox environment can result from cellular changes that result in diseases including cancer and cardiovascular conditions. As part of the EPSRC-funded redOx⇌KCL programme grant, our research involves the development of chemical tools that use optical- and radio-imaging techniques to provide real-time information on changes in the redox environment. Innovative tools will provide a platform to yield novel information on fundamental biological processes and new ways to predict or diagnose disease.
Targeting infectious diseases
Parasites are the cause of Chagas disease, leishmaniasis and schistosomiasis, three major neglected tropical diseases (NTDs) that affect millions of people in some of the poorest communities in the world. The parasitic species (Trypanosoma, Leishmania and Schistosoma) exist in different forms in their life cycle, allowing them to adapt to their changing habitats, which include the vector and the host bloodstream. We are investigating whether epigenetic mechanisms enabling changes in gene expression regulate the life cycle of parasites and ensure their survival. Bromodomains, ‘readers’ of lysine acetylation, have emerged as key gene expression regulators and a promising new class of drug target. Given that bromodomain-containing proteins play a fundamental role in regulating transcription in humans, we hypothesise that they will play equally important roles in parasites. We are investigating whether these proteins can be novel therapeutic targets to impede the life cycle of parasites and open new avenues for the treatment of infectious diseases.