Research within the Hodgkinson group is focused on the synthesis of novel chemical probes and compound libraries designed to study biological processes otherwise challenging by genetic approaches. Applications include; target identification, investigating novel ligand-protein interactions, enhancing membrane permeability, inhibitor design, and proteasome mediated targeted degradation. Our overall goal and vision is that our validated chemical probes will have direct applications for use by the members of chemical biology and biology communities in revealing new biology, studying disease and aiding drug discovery.
There are two main areas of research we are currently developing new chemical probes:
Epigenetics and HDAC modulation
Histone deacetylases (HDACs) are a family of enzymes that catalyze the removal of acetyl groups from lysine in both histone and non-histone proteins. The deacetylation of histones by HDAC’s results in structural modifications to chromatin which subsequently effects gene transcription. HDAC’s are classified into four in classes; I, IIa, IIb, III and IV. Class I HDAC’s exist in large multi-protein corepressor complexes that play important roles in many diseases including neurological disorders, immune disorders and cancer. HDAC’s and their multi-protein complexes have been targeted for inhibitor design as anti-cancer compounds. The pharmacodynamics of particular HDAC inhibitors are hypothesised to be dependent on the specificity of HDAC inhibition. Thus, opportunities are available towards the design and synthesis of isoform and even complex selective chemical probes by differing approaches, not solely by inhibition, but also by other methods in chemical biology such as targeted protein degradation. Collaborators include Professor John Schwabe (Dept. of Molecular and Cell Biology, University of Leicester) and Professor Shaun Cowley (Dept. Molecular and Cell Biology, University of Leicester).
Bacterial Iron transport
Siderophore transport and antibiotic delivery: Iron is integral to many biological processes in living organisms and is essential for bacterial survival. Bacteria secrete small molecules known as siderophores to chelate and scavenge iron from the surrounding environment. The siderophore-Fe(III) complex is recognized by receptor proteins on the outer membrane of bacteria and internalized into the bacterium cell by active transport. Thus, the synthesis of antibiotic-siderophore conjugates for active transport uptake into the bacteria cell has been demonstrated in instances to increase the potency of the antibiotic and also modify bacterial spectrum of activity. Research efforts in this project involve the synthesis of novel antibiotic-siderophore conjugates to identify molecules that can demonstrate enhanced uptake and antibiotic potency, and exhibit bacterial species selectivity. We are also interested in developing fluorescent imaging probes to monitor bacterial uptake of our conjugates. Collaborators include Professor Galina Mukamolova (Dept. of Respiratory Sciences, University of Leicester) and Dr. Martin Welch (Dept. Biochemistry, University of Cambridge).
Azotochelin-phenothiazine siderophore-antibiotic conjugate, A. Tarapdar et al., Beilstein J. Org. Chem. 2018, 14, 2646–2650.