Quick Project Snapshot
Drug discovery targeting α1-adrenoceptors (α1-ARs)
α1A- and α1B-adrenoceptors (α1A-AR and α1B-AR) are critical receptors that modulate the nervous system in response to binding adrenaline and noradrenaline, and are currently targeted by hypertension drugs. Chronic activity of these receptors can be either damaging or protective to heart and brain function and evidence suggests that these opposing responses are mediated by individual receptor subtypes. α1-ARs are the most abundantly expressed adrenoceptors in the CNS, where they serve as stimulatory receptors in post synaptic cell bodies. Stimulation of α1-ARs in these cells serves to increase the excitatory potential of glutamate and acetylcholine and to prime excitatory synapses. Transgenic mice have been used to demonstrate that α1A-AR and α1B-AR mediate opposing responses to noradrenaline release in the CNS. Whereas α1A-AR activation is antiepileptic, constitutive activation of α1B-AR is pro-epileptic. Similarly, α1A-AR stimulation increases neurogenesis whereas prolonged α1B-AR stimulation is neurodegenerative. The lack of subtype selective ligands makes the validation of these receptors as genuine targets for treating epilepsy, Parkinson’s disease and Alzheimer’s disease difficult. We have engineered thermostabilized α1A-AR and α1B-AR proteins that have enabled us to probe and compare the protein structures of these receptors. Furthermore we are able to conduct novel drug screening campaigns to identify subtype selective α1-AR compounds. In 2015, projects will be offered focused on identifying new α1-AR binding compounds with fragment screening as a starting point for structure based drug design. Students will be trained in techniques including protein structure analysis, computational ligand docking, protein expression and purification, robotic ligand binding assays, cell-based GPCR assays, nuclear magnetic resonance spectroscopy and pharmacological analysis. Ultimately, new α1-AR binding compounds may prove to be promising drug candidates for treating epilepsy and neurodegenerative diseases.
Receptor Structure and Drug Discovery Laboratory
Protein instability poses a major barrier to the characterisation and deployment of many proteins into industrial and biotechnological applications. Membrane proteins are a class of proteins that are particularly unstable, yet are highly important as they are the main targets for most prescription drugs. Membrane proteins are located on the surface of all types of cells and are involved in processes such as sensing neurotransmitters, driving neural impulses and responding to drug treatment. The instability of membrane proteins, however, makes them difficult to study. We use novel technology (CHESS) to engineer stabilised membrane proteins, particularly neuropeptide-binding G protein-coupled receptors (GPCRs), to aid in elucidating the atomic level mechanisms that govern their function and to facilitate novel drug discovery.
A particular focus of the laboratory is engineering members of the relaxin receptor family to enable greater understanding of how these receptors work at the molecular level and in turn enable the design of drugs targeting these important receptors. We also use this technology to engineer highly stable versions of other protein classes, such as fluorescent proteins and enzymes, for biotechnological and industrial applications.
All Projects by this LabEnabling technologies for structure based drug design at G protein coupled receptorsDesigning allosteric modulators of the neurotensin receptor 1 (NTS1) as potential drugs for schizophreniaDrug discovery targeting α1-adrenoceptors (α1-ARs)
The Neuropeptides Division primarily conducts multi-disciplinary studies on the relaxin family of peptides/hormones and their receptors. The division focuses on determining the role of these peptides and the receptors they target a wide range of physiological and disease states. These studies are coupled with fundamental drug discovery research on both these and other peptides and their G protein-coupled receptors. The aim of this research is to develop new biological knowledge and fundamental understanding about how to best therapeutically target these peptide systems with the long term view to develop drugs which target the peptide receptors to treat vascular, fibrotic, metabolic and psychiatric diseases.
An example of the success of this approach is the completion of a Phase III trial using the hormone relaxin for the treatment of acute heart failure by the Swiss Pharmaceutical Company Novartis. A Phase IIIb trial is ongoing and the relaxin drug, serelaxin, has been approved in Russia to treat patients with acute heart failure. Hence fundamental research on the mechanism of action of a hormone, in the case of relaxin pioneered at the Florey by the former Neuropeptides Division Head, Prof Geoffrey Tregear, can ultimately lead to its use to treat disease in patients.