GPCRs are 7-helical transmembrane proteins that are central to many biological processes and are the single most important family of drug targets in the human body. There are over 200 potential targets encoded in the human genome, and as many as 75 of these already have clinical validation. GPCRs represent important drug targets in all major therapeutic areas and are the site of action of 25-30% of current drugs, some with multi-billion dollar annual sales.
However, only six novel GPCR targets have been drugged with small-molecules in the past ten years, a fact which is mirrored by a lack of quality GPCR drug leads advancing through pharma pipelines. This represents a major opportunity for drug discovery both of small molecules and therapeutic antibodies.
In contrast to classes of soluble protein drug target, such as kinases and proteases, the discovery of new GPCR drugs has in many cases been severely hampered by the lack of structural and mechanistic knowledge of GPCRs and an understanding of how compounds interact with them.
The overriding problem is that GPCRs are very unstable and lose their highly organised structure and activity when taken out of the cell membrane. Until recently, this has prevented the production of stable, properly folded protein to which contemporary drug discovery approaches can be applied.
Heptares believes its broad in-house drug discovery capability, based around its breakthrough GPCR stabilisation StaR® technology, can emulate the success seen with the discovery of novel drugs targeting soluble enzymes and radically improve the chances of discovering safer and more selective drugs to previously intractable GPCR targets.
Complex of the human beta 2 adrenergic receptor and an antibody fragment
Acknowledgements:
Rasmussen et al. Nature. 2007 Nov 15;450(7168):383-7
Electron density around the cyanopindolol ligand binding site in the beta 1 adrenergic receptor.
Acknowledgements:
Warne et al, Nature. 2008 Jul 24;454(7203):486-91
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Crystal of a stabilised beta 1 adrenergic receptor
Acknowledgements:
Tony Warne, Maria Serrano Vega, Rouslan Moukhametzianov
Chris Tate and Gebhard F X Schertler Laboratory of Molecular Biology Cambridge
Electron density map of bovine rhodopsin. Krebs, A., Edwards, P.C, Villa, C., Li, J. and Schertler, G.F.X
The three-dimensional structure of bovine rhodopsin determined by electron cryomicroscopy. J. Biol. Chem. 278, 50217-50225 (2003)
Model of the crystal structure of bovine rhodopsin showing site of retinal binding
Acknowledgements:
Li J et al. J Mol Biol. 2004 Nov 5;343(5):1409-38
Structure of the beta1 adrenergic receptor.
Acknowledgements:
Warne et al, Nature. 2008 Jul 24;454(7203):486-91
Crystal packing of the beta 1 adrenergic receptor.
Acknowledgements:
Nature. 2008 Jul 24;454(7203):486-91.
Model of the cyanopindolol binding site in the beta 1 adrenergic receptor showing the interactions of the drug with the side chains of the receptor protein.
Acknowledgements.
Warne et al, Nature. 2008 Jul 24;454(7203):486-91
GPCRs are expressed in every type of cell in the body and play a critical role in linking messages from extracellular ligands to signalling pathways within the cell, between cells and between organ systems. GPCRs are drug targets in all major therapeutic areas and are the site of action of 25-30% of current drugs, some with multi-billion dollar annual sales.
The superfamily of GPCRs is defined by having 7-transmembrane spanning domains. These are activated by a wide variety of ligand types including protein and peptide hormones, peptide and small molecule neurotransmitters, metabolites, bacterial products and light.
Within the GPCR superfamily are a number of subfamilies that are linked by extensive amino acid similarity. These are:
Family A receptors: These include many neurotransmitter receptors, such as dopamine and adrenaline, peptide receptors such as opioid and neurokinin receptors, glycoprotein hormone receptors such as follicle stimulating hormone, and chemokine receptors such as CCR5, which is a target for HIV therapy.
Family B receptors: This family is activated by large peptide and protein ligands and plays a critical role in physiological processes such as appetite regulation, insulin signalling, stress and pain. The receptors are activated by ligands including glucagon-like peptide, calcitonin gene related peptide and corticotrophin-releasing hormone. Although many of these receptors are validated as disease targets through the use of protein therapeutics, to date few small molecule drugs are known to target this class.
Family C (metabotropic) receptors: This family is unusual in that members have very large extracellular domains. However, many of the drugs that are being developed for this class of receptors actually bind to the transmembrane domain and act as allosteric modulators. The metabotropic glutamate receptors are the largest subfamily within Family C and are important drug targets for a variety of neurological and psychiatric diseases.
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