PIONEERING PROGRESS ON GPCRS
Why Focus on GPCRs?
G-protein coupled receptors (GPCRs) represent the largest family of membrane proteins in the human genome, and the largest class of targets for drug discovery, as they mediate the majority of cellular response to hormones and neurotransmitters. Clinical indications for GPCRs include cardiovascular, pulmonary, metabolic, and psychiatric disorders, as well as inflammation, cancer, and HIV infection. More than 30% of currently approved drugs target GPCRs.
GPCRs are characterized by the presence of seven membrane-spanning alpha-helical segments separated by alternating loop regions that intracellularly bind G-protein’s alpha, beta, and gamma sub-units and extracellularly bind relevant ligands.
The Challenge
Since most of their surface is buried inside the membrane, GPCRs are notoriously difficult to crystallize, creating a major bottleneck to drug development due to the lack of high-resolution structural information on both functional conformations and potential binding sites. Despite very active academic and biopharmaceutical efforts around GPCRs over the past two decades, success in advancing new GPCR-targeted drugs has been limited.
The ConfometRx Solution
Based on the work of our co-founder, Dr. Brian Kobilka, and others, we have developed novel methods to determine the three-dimensional structures of GPCRs in inactive and active states. To date we have obtained multiple high resolution GPCR structures that have facilitated the discovery and optimization of lead candidates that are now advancing towards clinical studies.
Our proprietary methods center on our combined expertise in GPCR biochemistry, crystallography, and, most importantly, our experience and in-house capabilities in cryo-electron microscopy (cryo-EM). The use of cryo-EM is revolutionizing GPCR-targeted drug development, as we are able to, for the first time in many cases, elucidate the active-state structures of GPCRs that have defied crystallization.
Combining this technology and our patented protein fusion technology and ability to express, purify, and stabilize GPCRs in both inactive and active states, has enabled us to visualize the structure of receptors in physiologically and pharmacologically relevant conformations, thereby facilitating targeted drug discovery. To date, we have successfully employed cryo-EM to solve a series of iterative structures of GPCR-G protein complexes bound to various candidate compounds (both orthosteric and allosteric), reaching as high as 2.8Å resolution.
We are now continuing this work, producing structures with sufficient resolution, quality, and turnaround time to facilitate structure-based drug discovery and optimization, even for compounds with micromolar affinity, both in-house and for our partners.
