The ability to accurately design GPCR-targeting medicines with well-established mechanisms that avoid specific side effects within a therapeutic index — known as pathway-selective drug discovery — presents a unique opportunity with lower risk than utilizing traditional techniques to explore new, non-validated mechanisms.  Initial areas of focus for MEBIAS are Neuroscience/Pain, Metabolic, Gastroparesis, and Inflammatory-related disorders.

Native GPCR Purification and QC

Protein NMR in Solution

Current drug discovery approaches have been inadequate to rapidly design and develop pathway-selective GPCR agonists.  By applying its unique technology platform, MEBIAS can develop therapeutics avoiding GPCR-associated side effects.  At the core of their know-how to identify the next generation of GPCR drugs are two specialized technologies: Native GPCR purification and protein nuclear magnetic resonance.  This know-how allows MEBIAS to achieve sensitivity unmatched by cell-based assays alone.  The platform significantly decreases the time and expense to deliver preclinical candidates for IND pipelines.  Within the last 20 months MEBIAS has filed patent applications for two distinct chemotypes entering IND enabling studies.

Non-Constrained GPCR to Report Dynamics

Drugs targeting GPCRs make up ~30% of all FDA approved drugs.  While GPCRs play a key role in cell signaling affecting a wide range of physiology and diseases, the on-target adverse effects associated with drugs that activate GPCRs are also well established.  It was once thought that on-target side effects of GPCR drugs were unavoidable.  However, work over the past 15 years has revealed that GPCRs can be activated to signal differentially through distinct pathways and that designing drugs to activate just one pathway – pathway selective signaling – which will lead to efficacious drugs with fewer or no side effects.  Hence, there is an opportunity to capture a large share of existing GPCR drug markets by developing next generation, signaling-pathway selective compounds via the so-called ‘biased agonism’.  This approach is applicable to small and large molecules.  Examples of drugs with significant adverse effects targeting GPCR are: Mu-opioid receptor drugs (e.g. oxycodone for Analgesia), dopamine-2 receptor agonists (e.g. levodopa for Parkinson’s Disease), beta-1 adrenergic receptor (e.g., metropolol for Heart Failure), beta-2 adrenergic receptor (e.g., albuterol for Asthma), and motilin receptor (e.g., erythromycin for Gastroparesis).