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Heptares Release: Innovative Technology Enables First Crystal Structure Of A Class C GPCR Drug Target (mGLU5) Transmembrane Domain To Be Determined


7/17/2014 10:30:48 AM

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Several novel drug candidates have been identified to help treat specific neuropsychiatric disorders

Melbourn, UK, 17th July 2014. The first high-resolution X-ray crystal structure of the metabotropic glutamate receptor 5 (mGlu5) transmembrane domain was reported in Nature this week. The work was performed at Heptares Therapeutics, a leading drug discovery and development company using TTP Labtech’s innovative liquid handling technology for lipidic cubic phase crystallography (mosquito LCP).

Dr Andy Doré, Head of Crystallography at Heptares Therapeutics and joint first author of the recent article in Nature, stated, "the mosquito LCP was used for all crystallisation setups of the mGlu5-StaR resulting in us obtaining high resolution diffraction quality crystals for this receptor. The ability to reliably dispense low volume boli in 96 well LCP experiments using mosquito LCP is ideal for screening initial conditions and optimising this and other difficult targets."

mGlu5 is a member of the GPCR family of proteins and plays an essential part in neuronal signalling making it an important drug target for modulating cell function and influencing neuropsychiatric disorders. Metabotropic glutamate receptors are Class C GPCRs, which respond to the neurotransmitter glutamate and therefore are of considerable interest as drug targets 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 of mGlu5, providing little understanding of the membrane-spanning signal transduction domain, and hindering drug discovery efforts.

In this scientific publication the scientists at Heptares describe the crystal structure of the transmembrane domain of mGlu5 in complex with the negative allosteric modulator (NAM), mavoglurant. Heptares has used these new findings to identify several novel differentiated mGlu5 NAM drug candidates with improved potency and pharmacokinetic properties compared to previous candidate molecules.

To help increase the accuracy, speed and throughput of crystallography screening, optimisation and crystal production, TTP Labtech has engineered innovative automated liquid handling solutions, including the mosquito crystal and mosquito LCP, to significantly improve this process.

TTP Labtech's mosquito LCP is used by most of the world class institutions and leading pharmaceutical and biotechnology companies for protein crystallisation screening. It overcomes the common problems encountered with accurately dispensing the highly viscous LCP mixture used in membrane protein crystallisation. It allows you to fully automate LCP set-ups accurately and repeatedly and the technology has played an important role in the determination of many protein structures, including some key GPCRs.

"As early adopters of the mosquito LCP, we have had a close collaborative relationship with Dr Doré's team since 2010," commented Joby Jenkins, global director of automation at TTP Labtech. “The huge success of Heptares in determining ground breaking GPCR structures has resulted in increased productivity and the need for additional mosquito LCP instruments. We are delighted that our liquid handlers have been, and will be, an integral part of their ongoing success.”

About TTP Labtech – natural innovators

From its global headquarters based near Cambridge, UK, TTP Labtech is an employee owned company that creates, designs and manufactures robust and innovative automated laboratory equipment for both the academic and industrial sectors of pharmaceutical and biotech research.

TTP Labtech is part of TTP Group plc which originated from The Technology Partnership (TTP), Europe’s leading independent centre for innovation. For 13 years TTP Labtech has successfully combined cutting edge science with first rate engineering. Innovation is at the core of the company and is illustrated by the passion and expertise of its personnel and evidenced by the novel products and technologies that are brought to market.

TTP Labtech provides state-of-the-art solutions developed for specific product areas: cell-based screening (acumen®, mirrorball®); sample management (comPOUND®, arktic®, lab2lab) and low volume liquid handling (mosquito®, dragonfly®).

For further information please visit www.ttplabtech.com or download our free APP, available on iOS and Android.

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 www.heptares.com

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