Welwyn Garden City, UK. 19 May 2011 – Heptares Therapeutics today announced that the journal Nature has published results of joint research by scientists at Heptares and the MRC Laboratory for Molecular Biology (LMB, Cambridge, UK)) focused on the structures of G-protein coupled receptors (GPCRs) and their drug-binding sites. In the paper (ref. 1), the authors report the first-ever high-resolution structure of the adenosine A_2A receptor in its active signaling form and bound to its endogenous ligand, adenosine. This is the first time the structure of a GPCR has been resolved in its natural agonist-bound signaling form and represents an important scientific milestone in the field of GPCR biology and drug discovery.

The team from Heptares and LMB conducted the research using a proprietary technology for engineering stabilised receptors, or StaRs®. The prototype StaR® technology was invented at LMB and assigned to Heptares, where the technology has been developed, scaled-up, and applied to the discovery of novel GPCR-targeted medicines. 

The important results published today build upon a previous accomplishment by Heptares in determining the structure of the A_2A receptor in its inactive conformation (ref. 2). This achievement enabled Heptares to discover a completely novel A_2A antagonist candidate that exhibits best-in-class potential in the treatment of neurological disorders and is the subject of a recent partnership with Shire. 

“The scientific collaboration between Heptares and LMB continues to generate some of the most important and cutting-edge GPCR science in the industry today,” commented Malcolm Weir, CEO of Heptares. “The Nature publication illustrates how the StaR® approach delivers the natural and matched pair of structures for a GPCR, in both its active and inactive biological forms, so we now know in atomic detail how to distinguish between them. This is the ideal basis for GPCR drug discovery and is the approach Heptares is applying today across the broad GPCR super-family of drug targets.”

References

1)     Lebon, G. et al. Agonist-bound structures of the adenosine A_2A reveals common features of GPCR activation. Nature (2011) http://dx.doi.org/10.1038/nature10136

2)     Doré, A. et al. March 2011 International Patent Publication Number WO 2011/033322

About GPCRs & StaRs®

GPCRs comprise a super-family of drug targets that are linked to a broad range of diseases. Historically, the rational design of GPCR-targeted drugs has lagged behind the rational design of drugs aimed at other target families. A key obstacle has been the instability of GPCRs when removed from their natural locations on the surface of cells, which has made it difficult or impossible to determine the structure of many GPCR targets.

By stabilising the natural GPCR into a StaR® form, the GPCR’s structure can be determined through contemporary techniques such as Biophysical Mapping™ and x-ray crystallography. Heptares has generated StaRs® for over a dozen important GPCR targets that proved to be intractable to previous structural biology efforts due to their high instability.

GPCRs also exhibit different shapes, or “conformations,” depending if their signaling activity is activated or inhibited. Inhibition of the adenosine A_2A receptor, for example, increases neuronal activity of the neurotransmitter dopamine, with potential beneficial effects in patients with Parkinson’s disease and other neurological disorders where dopaminergic function is lost. Conversely, activation of A_2A enhances vasodilation. A full determination of the structure of a GPCR requires understanding how such differences in pharmacological effect correlate with conformational differences in structure. 

A unique advantage of the StaR® approach is the ability to stabilise GPCRs in each of their natural pharmacological conformations, so that even subtle structural variations can be detected and new areas within drug-binding sites can be revealed. The advanced understanding of GPCR structures enabled by StaRs® has allowed chemists at Heptares to design novel compounds that bind to specific, previously untargeted regions of GPCRs.