Celebrate_coverThroughout the summer, we’ve been showcasing a range of UK bioscience successes, taken from our recently published report Celebrating UK bioscience. As well as developing therapies, UK bioscience also develops, builds and commercialises the tools that Research and Development (R&D) scientists need to do their research. These platform businesses sell their techniques, kits and services to R&D labs in universities and competing global corporations. One example is the work developed by Heptares Therapeutics to unlock the potential of GPCR drug targets and the scientific research that has underpinned this.

G protein-coupled receptors (GPCRs) are proteins found embedded in the cell membrane. They act as a bridge between the interior and exterior environment of the cell. As such, they can transfer information in the form of biochemical signals. They play a role in many physiological and biological processes, including taste, vision, smell, autonomic nervous system function, mood, behaviour, immunity and tumour growth. GPCRs are, therefore, important drug targets and many of today’s current drugs target a GPCR, contributing to treatments for patients across a wide range of conditions, including asthma, high blood pressure, schizophrenia, migraine and leukaemia.

The challenge and the opportunity

The challenge surrounding GPCRs is that, like all membrane-bound proteins, they are very unstable outside of the membrane environment and are hard to crystallise. Drug discovery and development relies heavily on solving the 3-D structure of a target through x-ray crystallography, which then allows structure-based drug design (SBDD) to open the door to small molecule drugs that are safer, more potent and can become best or first in class in a therapeutic area.

A cross-section through a membrane showing a GPCR’s 7 transmembrane helices and a drug molecule (pink) binding in the middle

GPCRs represent a major class of targets, many of which are clinically validated, but which are currently not optimally ‘drugged’ – for existing compounds have limited potency and selectivity. There are also metabolic, safety and delivery issues around some of the GPCR drugs currently on the market.

Thus, not only is there room for development of best in class, there are also many high value GPCR targets which remain unexplored, so there are opportunities for first in class too, particularly in areas such as the central nervous system (CNS), metabolic diseases and cancer. Examples include the muscarinic receptor family, where “selective agonists” of the M1 and M4 receptors (drugs which bind to and activate those receptors), developed by Heptares, could treat cognitive impairment and psychosis (both significant symptoms of Alzheimer’s disease), respectively.

Another high value GPCR target is the adenosine A2A receptor, which plays a key role in dampening down the natural immune response to cancer. By blocking this process, A2A receptor antagonists (blockers) could be the basis of a novel approach to cancer immunotherapy.

The role of UK science in understanding and exploiting GPCRs

Scientists funded by the UK’s MRC and the pharmaceutical industry worked for many years to try to overcome the barriers to solving GPCR structures, taking key steps towards developing new treatments for patient benefit. Dr Christopher Tate, and colleagues, developed a groundbreaking technology which uses mutagenesis to stabilise GPCRs, and other membrane proteins, in a specific conformation or shape. In this original version of the technology, each amino acid residue in the GPCR is altered in turn and the thermostability of the resulting mutant protein is measured. The best mutations, i.e. most thermostable, are then combined to create a stable GPCR.

This technique was optimised by Heptares to create its StaR® technology. The stabilised GPCRs, or StaR® proteins, are purified and crystallised for x-ray crystallography. Importantly, the StaR® technology greatly improves the thermostability of a GPCR without disrupting its pharmacological properties, so that studies on it are still relevant to the drug discovery process. What’s more, the thermostabilised receptors can be crystallised in several different detergents and also with many different inhibitors or activators bound, so that the function of these receptors can be studied. SBDD can be started by the virtual screening of libraries of molecules to generate a number of hits which are then optimised using knowledge of the protein and ligand structures.

In 2007 Malcolm Weir and Fiona Marshall formed Heptares, as a spinout from the MRC Laboratory of Molecular Biology in order to further develop and commercialise the StaR® technology. The StaR® technology has been used to stabilise many GPCRs in all three main families (A, B and C) and to date has enabled Heptares to elucidate the x-ray structures of more than 10 GPCRs. Furthermore, the technology has potential beyond GPCRs and can open up other membrane proteins, such as the ion channels, to SBDD and the development of new, more effective and safer medicines.

“Heptares technology is the key to unlocking the potential of drug discovery targeting GPCRs, the most important target family in the human genome,” says Dr Malcolm Weir, Heptares CEO and Co-founder. “Our StaR® technology enables, for the first time, powerful structure-based approaches to be applied to discovering and precisely engineering novel small molecules that modulate GPCRs, while also providing stable protein for therapeutic antibody development. The successful creation of new medicines targeting GPCRs, given their crucial role in the body, has the potential to improve the treatment of severe and debilitating conditions that affect many millions of people around the world.”

Like to find out more? You can read the full version of the above story, along with five other case studies, in our report, “Celebrating UK bioscience: unravelling the stories behind UK bioscience success”.