STTR Phase I: A kinetic and conformation based platform for targeting G-protein coupled receptors

The broader impact/commercial potential of this Small Business Technology Transfer (STTR) Phase I project is to enable the discovery of new therapeutics targeting G protein-coupled receptors (GCPRs). GPCRs are expressed in nearly every organ system, are accessible due to their location on the membrane and potential to elicit almost every signaling pathway. Drugs targeting GPCRs make up 35% of all FDA approved drugs, generating sales of more than $200 billion annually. Despite relative success in pharmacologically targeting GPCRs they remain vastly underexploited, largely due to the lack of technology that addresses the characteristics and signaling patterns of GPCRs. The proposed project will explore the potential of GPCRs to help develop new drug candidates. This Small Business Technology Transfer (STTR) Phase I project leverages genetically encoded fluorescent GPCR sensor technology to address several challenging but necessary characteristics of GPCR targeted drug discovery: selectivity despite close sequence and structural homology, precise signal modulation within the continuum of receptor activation/ deactivation states and downstream signaling, in many cases the absence of a known endogenous ligand, and the ability to monitor compound activity (pharmacodynamics) directly in vivo in real-time. The proposed technology reflects ligand-dependent changes in GPCR conformation in real-time and directly reports ligand-receptor interactions, the primary determinant of signal generation in continuum. The technology can be readily implemented in high-throughput formats and universally adapted for a broad exploration of all GPCR targets. GPCR sensor technology provides unprecedented spatial and temporal resolution critical for in vivo analysis and enables precise measurements of the dynamic changes of receptor conformation. Therefore, it is well suited for the exploration of functionally selective compounds. Furthermore, by harnessing the sensitivity and selectivity of GPCR sensor technology, compounds that activate allosteric receptor sites through heterodimerization can be discovered. Ultimately, compounds discovered using the GPCR sensor technology are expected to be more clinically efficacious and therapeutically effective. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.