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Research by the School of Pharmacy has underpinned the development of fluorescent ligand probes that have opened-up new pathways in drug discovery. These ligands have been commercialised through the formation of the spin-out company CellAura Technologies Ltd, and have been made globally available through a number of distributer agreements. Customers include pharmaceutical companies (e.g. Pfizer, AstraZeneca), drug discovery biotechs (e.g. Addex, Heptares) and drug discovery technology providers (e.g. CisBio). These ligands provide alternatives to the use of radio-ligands, giving more informative and safer solutions for industrial drug discovery. This has, for example, enabled: a new direction in G protein-coupled receptor research at Novartis Pharmaceuticals UK Ltd; validation of Promega Corporation's new drug-binding assay; and superior performance in the establishment of cell lines at inSCREENex GmbH.
Original basic research on melatonin receptors undertaken at the Rowett Institute, University of Aberdeen, and funded by the Scottish Government, provided the opportunity for Servier pharmaceuticals to develop a new line of therapeutics for depression.
The company exploited Rowett know-how and invested in new research to develop a new line of compounds and to understand their structure-function relationships. This work enabled the development of melatonin analogues for clinical trials and ultimately led to the development of melatonin compounds for treatment of circadian related disorders.
One (S20098) was identified as having positive effects for disrupted circadian rhythms and beneficial outcomes for patients with depression. S20098 (also known as Agomelatine) was launched after EU authorization in 2009 as a novel anti-depressant drug called Valdoxan®. Today Valdoxan is an award winning anti-depressant drug recognised for its novel mechanism of action and few side effects. Valdoxan is the only anti-depressant drug to be brought to the market in the last 10 years. In summary, supported by investment from industry research undertaken at the University of Aberdeen contributed to the development of a novel antidepressant drug that provides a new clinical intervention with advantages over previously available antidepressants that will make a significant impact on the health and well-being of those afflicted by depression.
Research by Professor Kevin Fone in the Neuroscience group has established and characterised rodent models of CNS disorders that have been instrumental in validating several 5-hydroxytryptamine (5-HT) receptors as therapeutic drug targets to treat learning and memory dysfunction in humans. Specifically, animal studies to validate the 5-HT6 receptor for cognitive impairment in Alzheimer's disease (AD), depression and schizophrenia have resulted in R&D investment in drug discovery programmes by several global pharmaceutical companies. Consequent advances in healthcare benefits (current and potential) are also summarised.
Professor Geoffrey Burnstock and colleagues' establishment of the molecular structure of the P2Y class of receptor led to the cloning of several receptors within this class, which are increasingly seen as therapeutic targets for a variety of disorders. Indeed, drugs acting at these receptors are already improving patient health worldwide by reducing the risk of thrombotic events in people suffering from myocardial infarction or ischaemic stroke (via P2Y12 receptor antagonists) and by relieving the symptoms of dry eye disorder (via P2Y2 receptor agonists). Burnstock and colleagues also cloned the P2X3 receptor which mediates pain information, and P2X3 antagonists are being developed as novel analgesics. As well as clear clinical benefits, these drug developments are associated with substantial economic and commercial benefits.
Research led by Dr. Peter Richardson in the Department of Pharmacology led to the development of an A2A adenosine receptor antagonist (istradefylline) for the treatment of Parkinson's disease. In 2001, Dr Richardson founded the spin-out company Cambridge Biotechnology (CBT) to develop these drugs. A pH-sensitive adenosine A2A receptor agonist is now being developed for the treatment of neuropathic pain, with one product licensed for use in Japan in 2013 (Nouriast). Small-molecule leptin mimetics as potential anti-obesity drugs were also developed, initially by CBT and since 2009 by Astra Zeneca following acquisition of the research programme. CBT has undergone a number of high-value acquisitions, by Biovitrium, Proximagen, and most recently Upsher-Smith. It continues to operate as a wholly-owned subsidiary, employing 30-35 people from 2001 to the present.
Fluorescent ligand technologies developed by Professor Hill and Dr Briddon in the Pharmacology research group, in collaboration with Professor Kellam in the School of Pharmacy, permitted biophysical analysis of G-protein coupled receptors (GPCRs) at the individual cell and molecule level for the first time. The technologies have been commercialised through the spin-out business, CellAura Technologies (and their distributors Abcam, Sigma-Aldrich and others), generating revenues and making the products available to researchers and drug discovery communities worldwide. Custom product developments with global pharmaceutical companies and drug screening reagent providers have generated further partnership revenues and technology benefits. Nottingham-trained researchers are now employed worldwide, broadening the technology's impacts.
Members of the Pharmacology Research Group identified hitherto unknown properties of G protein Coupled Receptors (GPCRs): that ligands can signal differentially through both G-protein-coupled and β-arrestin pathways. This led to the concept of GPCR `biased signalling' and development of fluorescent reporters to quantify β-arrestin signalling. These discoveries have been adopted widely by the pharmaceutical industry, attracting R&D investment and collaborative research funding, to drive discovery of new drugs operating through `biased signalling'. The commercial opportunity has also been exploited by screening reagent providers and contract screening organisations. These discoveries will ultimately produce better drugs to treat GPCR-based diseases to improve human health.
The Farndale group have identified fragments of collagen, synthesised and assembled in active, triple-helical conformation, for use as ligands to manipulate platelet function. As a result of this work, the fragment Collagen-Related Peptide (CRP) is included in British Committee for Standards in Haematology guidelines as a platelet agonist for the diagnosis of platelet defects. The group has also synthesised triple-helical collagen peptide libraries and used them to map binding of cells or proteins to collagen more widely. The peptides are made and distributed by the Farndale lab, generating income through sales and licencing, and are used internationally by companies and hospitals to develop diagnostics and for high-throughput drug discovery. Prof Farndale also acts as a consultant for companies developing diagnostics.
The Guide to Receptors and Channels has contributed to the development and maintenance of the intellectual infrastructure of pharmacology. The key tools it provides have influenced appropriate identification of lead drug targets and how best to study them and, as a result, it has received endorsement and financial support from the Pharmaceutical Industry. It is used widely as a teaching aid for undergraduates and research postgraduates and provides the general public with accurate information on prescription drug action. It led to the formation of the Guide to Pharmacology website in collaboration with the International Union of Basic and Clinical Pharmacology.
A new anti-inflammatory molecule FX125L was developed by David Fox at Warwick, in collaboration with David Grainger (Department of Medicine, Cambridge) and Funxional Therapeutics Ltd (FXT). Research in lead optimization, mechanistic preclinical chemistry, synthetic route development (for scale-up), and CMC (chemistry, manufacturing and controls) was conducted at Warwick. As a result FX125L completed Phase 1 and entered Phase 2 clinical trials in humans for the treatment of asthma or other inflammatory diseases. Its sale to Boehringer Ingelheim generated a multi-million pound return for FXT and its investors.