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

这个小企业技术转让（STTR）I期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（GCPR）的新疗法。GPCR在几乎每个器官系统中表达，由于其在膜上的位置和引发几乎所有信号传导途径的潜力而可接近。靶向GPCR的药物占FDA批准的所有药物的35%，每年的销售额超过2000亿美元。 尽管在靶向GPCR的生物技术方面取得了相对成功，但它们仍然被大大地开发不足，这主要是由于缺乏解决GPCR的特征和信号模式的技术。拟议项目将探索GPCR的潜力，以帮助开发新的候选药物。这个小企业技术转让（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接近，但仍具有选择性，在受体活化/失活状态和下游信号传导的连续体内精确的信号调节，在许多情况下缺乏已知的内源性配体，以及直接在体内实时监测化合物活性（药效学）的能力。所提出的技术实时反映了GPCR构象的配体依赖性变化，并直接报告了配体-受体相互作用，这是连续信号产生的主要决定因素。该技术可以很容易地以高通量形式实施，并普遍适用于对所有GPCR靶标的广泛探索。GPCR传感器技术提供了对体内分析至关重要的前所未有的空间和时间分辨率，并能够精确测量受体构象的动态变化。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，可以发现通过异二聚化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上更有效，治疗效果更好。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值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.