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Heptares Scientists Solve Structure of Complement C5a Receptor, an Important Drug Target for Inflammatory and Neurodegenerative Diseases, and Cancer


News provided by

Heptares Therapeutics and Sosei

04 Jan, 2018, 08:00 GMT

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TOKYO and LONDON, January 4, 2018 /PRNewswire/ --

Publication in Nature highlights opportunities to target C5a receptor with selective small molecules via novel mechanism of action  

Sosei Group Corporation ("Sosei"); TSE Mothers Index:4565) announces that scientists at its wholly owned subsidiary, Heptares Therapeutics, have published the first high-resolution X-ray crystal structure of the complement C5a receptor (a G protein-coupled receptor, GPCR) binding a small molecule allosteric antagonist.

The findings, published in Nature today, reveal the location of a new allosteric binding site outside the transmembrane helical bundle and provide insights to the mechanisms by which small molecules interact with and modulate the receptor. This research further emphasises the potential importance and value of structure-based methods to enable the design of selective and optimised small molecules targeting GPCRs for treating a range of diseases.

The C5a receptor (C5a anaphylatoxin chemotactic receptor 1, also known as CD88) plays a key role in the innate immune response. It is part of the complement system, a crucial component of the host response to infection and tissue damage. Activation of the complement cascade generates anaphylatoxins, including the glycoprotein C5a, which exerts a pro-inflammatory effect via the C5a receptor.

Inhibitors of the complement system are of interest as potential drugs for treating diseases including sepsis, rheumatoid arthritis (RA), Crohn's disease and ischaemia-reperfusion injuries. More recently a role of C5a in neurodegenerative conditions such as Alzheimer's disease has been identified. C5a also plays a role in cancer through actions on tumour cells, angiogenesis and regulation of the immune cells in the tumour microenvironment. Peptide antagonists based on the C5a ligand have been evaluated in clinical trials in psoriasis and RA, however these peptides exhibited problems with off target activity, production costs, potential immunogenicity and poor oral bioavailability.  

Fiona Marshall, Chief Scientific Officer of Heptares and Sosei, said: "Our ability to determine the structures of GPCRs with high definition alongside our other structure-based drug design technologies and expertise provides a unique opportunity to tackle high value but difficult targets. With the C5a receptor, these capabilities and the insights they generate provide opportunities to design novel and selective therapeutics to address areas of clear medical need."

Reference 

Robertson, N et al. Structure of the complement C5a receptor bound to the extra-helical antagonist NDT9513727 (2018) Nature 553, 111-114 (doi:10.1038/nature25025)

Notes to Editors 

About Sosei 

Sosei Group Corporation is an international biopharmaceutical company originating from Japan that discovers and develops innovative biopharmaceuticals for the treatment of Alzheimer's disease, schizophrenia, cancer, migraine, addiction, metabolic disease, and other indications. By utilizing its GPCR structure-based drug design platform technology, Sosei has established a product pipeline with first/best in class potential. Through development and commercialization partnerships, Sosei has already delivered two bronchodilators for COPD which generate significant and stable revenue streams that enable further growth. Sosei partners include Novartis, Allergan, AstraZeneca, MedImmune, MorphoSys, Teva, and Pfizer and we are actively looking for new partnerships to enhance the development of our products and help us deliver them to patients worldwide.

For further information about Sosei, please visit http://www.sosei.com/en/.

Sosei Group Corporate Forward-looking statements  

This press release contains forward-looking statements, including statements about the discovery, development and commercialisation of products. Various risks may cause Sosei's actual results to differ materially from those expressed or implied by the forward-looking statements, including: adverse results in clinical development programs; failure to obtain patent protection for inventions; commercial limitations imposed by patents owned or controlled by third parties; dependence upon strategic alliance partners to develop and commercialise products and services; difficulties or delays in obtaining regulatory approvals to market products and services resulting from development efforts; the requirement for substantial funding to conduct research and development and to expand commercialisation activities; and product initiatives by competitors. As a result of these factors, prospective investors are cautioned not to rely on any forward-looking statements. We disclaim any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.

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