Heptares Announces Publication in Nature of First Structure of Metabotropic Glutamate Receptor 5 Transmembrane Domain

LONDON and BOSTON, July 7, 2014 /PRNewswire/ --

Heptares has solved structures across all major GPCR families (A, B and C) providing platforms for wide-ranging structure-based and antibody drug discovery programmes 

Heptares Therapeutics, the leading GPCR structure-guided drug discovery and development company, announces the publication of a scientific article describing the first high-resolution X-ray crystal structure of the transmembrane domain of the metabotropic glutamate receptor 5 (mGlu5). The paper was selected for Advanced Online Publication in Nature (Doré, A.S. et al, ref. below).

Metabotropic glutamate receptors are Class C GPCRs, which respond to the neurotransmitter glutamate. mGlu5 is of considerable interest as a drug target for the treatment of a range of diseases, including Fragile X syndrome, autism, depression, anxiety, addiction and movement disorders. Structural studies to date have been restricted to the extracellular domain, providing little understanding of the membrane-spanning signal transduction domain, and hindering drug discovery efforts.

In this paper, the authors from Heptares describe the crystal structure of the transmembrane domain of mGlu5 in complex with the negative allosteric modulator (NAM), mavoglurant. The structure provides detailed insight into the architecture of the transmembrane domain of mGlu5 including the precise location of the allosteric binding site within the transmembrane domain and key micro-switches that regulate receptor signaling.

Heptares has used these new findings to identify several novel differentiated mGlu5 NAM drug candidates with improved potency and pharmacokinetic properties compared to previous molecules. In addition, owing to the close relationship among Class C GPCRs, the enhanced knowledge of the mechanism of action of allosteric modulators for metabotropic glutamate receptors will enable the design of both negative and positive allosteric modulators by providing a template for homology modeling of other Class C GPCRs.

Fiona Marshall, Chief Scientific Officer at Heptares, commented: "Heptares has now published pioneering research describing the use of its StaR® platform for elucidating the structures of key members of all major GPCR families: A, B and C. These structures greatly enhance our ability to identify conserved and divergent structural and mechanistic features for each family and provide a strong basis for advancing structure-based drug discovery programmes."

Reference 

Andrew S. Doré et al. Structure of the class C GPCR metabotropic glutamate receptor 5 transmembrane domain, 2014, Nature http://dx.doi.org/10.1038/nature13396

About Heptares Therapeutics 

Heptares creates new medicines targeting clinically important, yet historically challenging, GPCRs (G protein-coupled receptors), a superfamily of drug receptors linked to a wide range of human diseases. Leveraging our proprietary structure-based drug design technology platform, we have built an exciting pipeline of novel drug candidates with the potential to transform the treatment of serious diseases, including Alzheimer's disease, ADHD, diabetes, schizophrenia, and migraine. Our pharmaceutical partners include Cubist, MorphoSys, Takeda, AstraZeneca and MedImmune, and we are backed by Clarus Ventures, MVM Life Science Partners, Novartis Venture Fund, the Stanley Family Foundation and Takeda Ventures. To learn more about Heptares, please visit http://www.heptares.com

HEPTARES is a registered trademark in the EU, Switzerland, US and Japan;  

StaR is a registered trademark in the EU and Japan.