Synthetic organic chemistry and chemical biology
My research group is focused on the chemical synthesis of new diverse molecular probes and compound libraries specifically tailored to study biological processes at a molecular level. Applications of such probes and libraries include; mode of action(s) studies, investigating novel ligand-protein interactions, overcoming membrane permeability, inhibitor design and selective targeted degradation by the proteasome. The overall aim is to understand how the biological processes under investigation can be altered and regulated with structural modifications to the small molecule probe.
In collaboration with Professor Shaun Cowley and Professor John Schwabe current biological macromolecules under study with novel chemical probes include epigenetic protein complexes. Such large multi-protein complexes, involved in chromatin modification, play important roles in many diseases including neurological disorders, immune disorders and cancer. A novel approach we are interested in is the synthesis and design of PROTACs (Proteolysis Targeting Chimeras) to specifically target epigenetic protein complexes for ubiquitination and subsequently proteasome mediated cellular degradation. PROTAC molecules typically incorporate a ligand for recognition by the protein of interest separated by a linker moiety that is covalently tethered to an E3 ligase ligand. Other approaches include the design and synthesis of peptides tailored to act as ‘molecular glue’ to stabilise such protein complexes for further biochemical studies.
My research group also has a keen interest in the design and synthesis of siderophore molecular probes to study iron transport in pathogenic bacteria. The siderophore-iron complex is recognized by specific 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 to increase the potency of the antibiotic and also broaden bacterial spectrum of activity.
- Geddis SM, Coroama T, Forrest S, Hodgkinson JT, Welch M, Spring DR. (2018) Synthesis and biological evaluation of
- 1,2-disubsubstituted 4-quinolone analogues of Pseudonocardiasp. natural products. Beilstein J Org Chem.14:2680- 2688.
- Tarapdar A, Norris JKS, Sampson O, Mukamolova G, Hodgkinson JT. (2018) The design and synthesis of an antibacterial phenothiazine-siderophore conjugate. Beilstein J Org Chem.;14:2646-2650.
- Y. R. Baker et al. (2017) 'Identification of new quorum sensing autoinducer binding partners in Pseudomonas aeruginosa using photoaffinity probes' Chem Sci, vol. 8. Pp. 7403-7411.
- Hodgkinson JT, et al. (2016) 'A new Pseudomonas quinlone signal (PQS) binding partner: MexG'. Chem Sci, vol. 7. Pp. 2553-2562.
- Hodgkinson JT, et al. (2012) 'Microwave-assisted preparation of the quorumsensing molecule 2-heptyl-3- hydroxy-4(1H)-quinolone and structurally related analogs.' Nat Protoc, vol. 7. Pp. 1184-1192.
Jasmine Cross, Stuart Hodgkinson, James Norris and Josh Smalley