Heptares and leadXpro to employ powerful new techniques for GPCR structure determination

Heptares Therapeutics and leadXpro are to employ powerful new approaches for the determination of high-resolution X-ray structures of G protein-coupled receptors (GPCRs) to discover new drug lead compounds.

GPCRs form one of the most important classes of drug targets, and Heptares is a world leader in the use of structure-based methods for GPCR drug discovery. leadXpro has deep expertise in biophysical and structure-based methods including serial crystallography and cryo-electron microscopy (cryo-EM), and applies these new techniques to the discovery and optimisation of innovative lead compounds targeting membrane proteins, such as GPCRs, ion channels and transporters.

In the collaboration, Heptares will use its proprietary platform to generate conformationally stabilised GPCRs (StaR proteins), which facilitate the formation of protein crystals.  The teams will evaluate novel analytical methods for crystals that fail traditional X-ray crystallography techniques, using leadXpro’s expertise in high-powered X-ray technology at Swiss Light Source and free-electron laser technology at SwissFEL. This combination of technologies has the potential to accelerate the delivery of structural information for drug discovery efforts.

Powerful new techniques that could open many new opportunities

Commenting on the collaboration, Michael Hennig, Chief Executive Officer of leadXpro, said: “We are excited Heptares has chosen to collaborate with us and to apply leadXpro’s unique technological capabilities to complement its StaR protein and structure-based drug design platform. Serial crystallography with synchrotron and free electron laser technologies push the frontier of membrane protein crystallography. Advantages include enhanced X-ray data collection at room temperature and the ability to generate more than 100-fold redundancy of data, while the ultimate brilliance of the free electron laser enables work with much smaller crystals to produce better resolved 3D structures. In this way we can unlock those membrane proteins that are currently intractable for structure-based drug discovery.”

Fiona Marshall, Heptares’ Chief Scientific Officer, added: “Serial crystallography and free electron laser technology are powerful new techniques that could open many new opportunities for drug discovery when applied to StaR proteins. This collaboration is a further demonstration of our commitment to remain at the forefront of GPCR structure based drug discovery.”