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

这个小企业技术转移(STTR)第一阶段项目的更广泛的影响/商业潜力是能够发现针对G蛋白偶联受体(GCPRs)的新疗法。GPCRs在几乎每个器官系统中都有表达，由于其在细胞膜上的位置以及可能引发几乎每一条信号通路，因此是可获得的。针对GPCRs的药物占FDA批准的所有药物的35%，每年产生超过2000亿美元的销售额。尽管在药物靶向GPCRs方面取得了相对成功，但它们仍然严重未得到充分利用，这主要是由于缺乏解决GPCRs的特征和信号模式的技术。拟议的项目将探索GPCRs的潜力，以帮助开发新的候选药物。这个小型企业技术转移(STTR)第一阶段项目利用基因编码的荧光GPCR传感器技术来解决GPCR靶向药物发现的几个具有挑战性但必要的特征：尽管序列和结构同源性很近，但仍具有选择性，受体激活/去激活状态和下游信号连续统内的精确信号调制，在许多情况下缺乏已知的内源性配体，以及能够实时直接在体内监测化合物的活性(药效学)。所提出的技术实时反映GPCR构象中配体依赖的变化，并直接报告配体-受体相互作用，配体-受体相互作用是连续统中信号产生的主要决定因素。这项技术可以很容易地以高通量格式实施，并普遍适用于对所有GPCR目标的广泛探索。GPCR传感器技术提供了前所未有的空间和时间分辨率，对于活体分析至关重要，并使精确测量受体构象的动态变化成为可能。因此，它非常适合于功能选择性化合物的探索。此外，通过利用GPCR传感器技术的灵敏度和选择性，可以发现通过异源二聚激活变构受体位点的化合物。最终，使用GPCR传感器技术发现的化合物有望在临床和治疗上更有效。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.