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On demand webinar

Unprecedented fragment-based screening using Spectral Shift for GPCRs

In this webinar, we will present how challenging recombinant protein such as GPCRs are produced and characterised and how biophysics participates in GPCRs hit finding and hit confirmation.

Fragment-based drug design presents a unique opportunity to identify novel binding sites for membrane proteins. We leveraged fragment screening using the most recent biophysical technology, Spectral Shift, to discover antagonist hit fragments on the human adenosine A2A receptor. 

Specifically, we will outline how our experts and internal capabilities can speed up your drug discovery processes taking advantage of their expertise in GPCRs protein production and screening with the most recent biophysics technologies.

Fragment-based drug design presents a unique opportunity to identify novel binding sites on membrane proteins. We leveraged fragment screening using the most recent biophysical technology, Spectral Shift, to discover antagonist hit fragments on the human adenosine A2A receptor. This receptor belongs to the G-protein-coupled receptor (GPCR) family, expressed in the plasma membrane of neurons and immune cells, including macrophages, cytotoxic and regulatory T cells. Its abnormal expression in immune cells inhibits the immune response and promotes the growth and escape of tumour cells from immune cells. Eurofins CALIXAR optimised the production of the wild-type, full-length, and active recombinant protein solubilised from Sf9 insect cells using Eurofins CALIXAR proprietary detergents.

We will highlight the advantages of Spectral Shift technology, one of the possible approaches using the Dianthus (well-known for the MST-TRIC). Using Echo® acoustic droplet ejection, and specifically nanoliter dispensing in 384-well plates, robust data by Spectral Shift were generated for the fragment-based screening campaign with a 9.2 percent hit rate. Among 86 fragments, 20 fragment hits were confirmed by dose-response testing, with µM-range affinity values. NanoDSF was then used as an orthogonal assay for the identification of stabilisers.

Additionally, the fragment hits were tested with one of our cellbased LeadHunter® assays (A2A receptor), and interestingly, some were found to be antagonists at high concentration with very good ligand efficiency. Docking studies to identify the fragment binding sites are currently ongoing. The starting points will be used as the basis for fragment growing.

Key learning points: 

  • Discover new hit finding strategy for GPCR drug discovery
  • Learn how high-quality recombinant protein is key for fragment-screening success
  • Increase the success rate to identify innovation hit starting points with the Eurofins Discovery Fragment library
  • Our biophysical platform comprises the state-of-the-art equipment required for screening cascade and binding confirmation. 

Watch on demand now!

OUR SPEAKER

Vanessa Porkolab, PhD – Biophysics Director, Eurofins Discovery

Dr Porkolab manages the Biophysics Platform for drug discovery projects at Eurofins Cerep. Prior to joining as Biophysics Director in 2022, she was Team Leader, Senior Scientist in Biophysics in another European CRO and Biotech working on fragments, small-molecules, antibodies and aptamer-based drug discovery programmes. With her scientific team, she is involved in integrated projects spanning target validation, high-throughput screening campaigns and hit-to-lead to lead optimisation. She completed her PhD at the Institut de Biologie Structurale (IBS) in Grenoble, France where she worked on multidisciplinary drug design projects targeting carbohydrate-based proteins involved in the immune response. She then moved to Brandeis University near Boston, USA where her postdoctoral studies were focused on RNA display and biophysical characterisation of glycopeptides for anti-HIV Abs.

Alexis Moreno, PhD – Research Scientist, Eurofins CALIXAR

Dr Moreno is a biochemist with expertise in membrane protein science. He holds a PhD in Biochemistry from the University of Lyon, France. Currently Scientific Project Leader at Eurofins CALIXAR, Alexis oversees the development of challenging recombinant membrane targets, such as GPCRs, for drug discovery applications. 

Maud Sigoillot, PhD – Research Scientist, Eurofins Discovery

Dr Sigoillot is a Project Leader for Biophysics Projects. She works closely with clients to define the most effective biophysical strategy and is responsible for the integrity of the scientific data of the project. Dr Sigoillot obtained her PhD at the University of Burgundy in 2011, specialising in the perception of sweet and umami tastes mediated by G-Protein Coupled Receptors (GPCRs). Subsequently, she deepened her knowledge of GPCR biochemistry during a first postdoctoral experience at Tsinghua University (China). Back in Europe, she focused on engineering nanobodies to treat cystic fibrosis at the University of Brussels (ULB, Belgium) and had the opportunity to join Chromacure a biotech, as a Research Scientist to develop complementary biophysical assays targeting orphan nuclear receptors in the context of drug discovery programmes in oncology. 

FAQs

Is the webinar free?
Yes – there is no charge to watch the webinar.

How long will the webinar be?
This webinar will last for up to one hour.

What do I need to watch this webinar?
All you need is a computer with an internet connection. Be sure to use headphones if in an office environment.

Do I receive a certificate?
Yes, you will receive a certificate if you attend the webinar live. The certificate will be sent with your on-demand video link.