Proprietary Research Platform

Sosei Heptares has built a unique and powerful platform capability that for the first time enables:

  • Engineering of functional, stabilized GPCRs (StaR® proteins) in their natural pharmacological conformations (agonist or antagonist), including orphan receptors
  • Determination of 3D structures of GPCRs and complexes with bound ligands by X-ray crystallography, Cryo-EM and Biophysical Mapping™
  • Deployment of advanced fragment-based drug discovery (FBDD) approaches to GPCRs
  • Full integration of GPCR pharmacology and medicinal chemistry
  • Design of novel agents directed towards high-value yet historically challenging or undruggable GPCR drug targets

StaR® 

StaR® (Stabilized Receptor) technology forms the backbone of Sosei Heptares’ integrated SBDD platform that enables us to “unlock” the potential of GPCRs through an advanced understanding of their structure.

Our StaR® technology allows us to stabilize a GPCR by engineering a small number of single point mutations outside of the ligand-binding site such that they retain their organized structure even after they are removed from the cell membrane. The resulting stabilized proteins (StaR® proteins) are much more robust than the corresponding “wild-type,” or unmutated, proteins. These StaR® proteins are more readily purified and subjected to a variety of hit discovery and biophysical approaches.

For example, StaR® proteins enable crystallization for detailed X-ray (or other) structure determination, which facilitates the design of innovative medicines with better safety and efficacy profiles and lower preclinical and clinical attrition rates compared to wild-type proteins. StaR® technology also enables the production of stabilized proteins that can be used for biologics discovery, either via in vitro phage screening, or for in vivo immunization.

CHESS

CHESS technology employs molecular evolution techniques to rapidly evolve panels of GPCR variants, each closely resembling the original target GPCR, and with enhanced stability and versatility for applying SBDD.

CHESS evolves functional stabilized GPCRs from populations containing hundreds of millions of variants of an ancestor GPCR, ensuring the identification of the best possible variant for drug discovery applications. When applied to an attractive GPCR, CHESS delivers correctly folded GPCRs that can be purified and stored in a ligand-unbound state. These GPCRs can be expressed using inexpensive hosts, such as E. coli, to produce high-quality protein in order to accelerate drug discovery. CHESS delivers GPCR targets that are stable enough to conduct high-throughput drug screening and selection of biologics, as well as various structural and biophysical techniques.

SaBRE

Similar to CHESS technology, SaBRE employs molecular evolution techniques to rapidly evolve panels of GPCR variants, each closely resembling the original target GPCR, and with enhanced stability and versatility for applying SBDD.

SaBRE (Saccharomyces cerevisiae-Based Receptor Evolution) expands the directed evolution technology to a eukaryotic host, which allows the generation of improved receptor variants of even the most difficult-to-express members of the GPCR superfamily.


Discovery

New Chemical Entity Discovery

Our technology, for the first time, allows powerful, precision SBDD methods to be applied to design of novel small molecules and peptides that modulate historically undruggable or challenging GPCRs. These techniques, which are routinely used for soluble enzyme targets, can now be applied to StaR® protein from early screening of chemical libraries, through hit selection and lead optimization.

Antibody Discovery

GPCRs are implicated in a wide variety of diseases where antibody therapeutics are currently used, such as inflammatory disease, metabolic disease and cancer. However, to date only one GPCR-targeted antibody has been approved and the pipeline for GPCR-targeted antibodies is sparse. This innovation gap reflects significant challenges unique to GPCR-focused antibody drug discovery.

StaR® proteins enable antibody discovery by stabilising the GPCR protein outside the cellular membrane and maintaining the correct receptor folding. StaR® proteins preserve all biologically relevant epitopes and allow a diverse panel of functional antibodies to be obtained when used as antigen for in vivo immunization. This has previously proved impossible for GPCRs, which lose their conformational and functional integrity when removed from their natural environment in cell membranes.

We use ‘state of the art’ automation to support our compound management and Drug Discovery approach