Selective modulation of GPCR signal transduction with biased ligands

描述（由申请人提供）：目前FDA批准的药物中约有三分之一作用于G蛋白偶联受体（GPCR），共同影响全球数亿人。这些药物是基于有限的信号传导模式开发的，通过该模式，激动剂对受体的刺激导致通过异源三聚体G蛋白激活从受体发出的所有细胞内信号传导途径。然而，最近已经证明，GPCR不仅以这种简单的方式发出信号，而且还激活了由平行信号转导途径组成的下游效应网络。现在提出，偏向于诱导或阻断特定信号传导途径的GPCR配体与无偏向的分子相比将具有差异化的生理学，通过选择性接合信号级联的期望子集以递送独特的有益效果组，所述有益效果组可以与通常由正构激动剂表现出的不期望的效果分离。这种功能选择性可以提供一种机制，通过激活或抑制相关的信号转导途径，开发具有更精确靶向作用的新药。该项目的主要目标是识别和表征各种GPCR的功能选择性偏向配体，并将其提供给科学界，以快速加速和扩大对功能选择性的理解和利用，作为开发新的更好药物的途径。在特定目标#1中，我们将选择12个GPCR，并将设计、优化和部署一套检测方法，以识别针对每种受体的偏倚配体。将对选定的GPCR进行稳健且经验证的筛选过程，通过该过程将鉴定这些GPCR的偏倚配体。在具体目标#2中，我们将研究所选的偏向配体，以改善其偏向性，效力和受体选择性。这种大规模的筛选、优化和表征项目将大大增加可用于进一步研究和开发的有效偏置配体的数量，无论是作为研究工具还是作为潜在的治疗候选物。该项目产生的科学知识有可能从根本上改变研究人员对GPCR生物学及其在疾病中的作用的看法，并定义GPCR配体本身在未来被识别，分析和分类的方式。将向GPCR社区提供功能选择性配体，以进一步研究特定的GPCR信号转导途径。这将大大增强理解和欣赏功能的选择性，使广泛的体外和体内实验。特别是，我们期望该项目将促使对功能选择性和非选择性GPCR配体药理学的理解迅速发展，并能够探索功能选择性分子影响药理学疗效，耐受性和新药发现工作的不良反应的潜力。 公共卫生相关性：目前FDA批准的药物中约有三分之一作用于G蛋白偶联受体（GPCR），共同影响全球数亿人。在这个应用中，Trevena提出证明功能选择性偏向配体的广泛适用性，这些配体仅激活源自GPCR的特定途径，从而将GPCR激活的有益效果与其产生的不良影响分开。这个项目产生的科学知识有可能从根本上改变研究人员对GPCR生物学及其在疾病中的作用的看法，并重新定义GPCR配体本身在未来被识别、分析和分类的方式。该项目有助于推进NIH改善健康的使命，因为它将迅速加速发现新一代改进的GPCR药物。

DESCRIPTION (provided by applicant): Roughly one third of today's FDA-approved drugs act on G-protein coupled receptors (GPCRs), collectively affecting hundreds of millions of people worldwide. These medications were developed based on a limited signaling paradigm, by which stimulation of the receptor by an agonist leads to activation of all intracellular signaling pathways emanating from the receptor via a heterotrimeric G-protein. However, it has recently been demonstrated that GPCRs do not only signal in this simplistic fashion, but rather activate a network of downstream effects comprised of parallel signal transduction pathways. It is now proposed that GPCR ligands that are biased towards induction or blockade of specific signaling pathways will have differentiated physiology compared with unbiased molecules, through selective engagement of a desired subset of signal cascades to deliver a unique set of beneficial effects that can be separable from the undesirable effects generally exhibited by an orthosteric agonist. Such functional selectivity may provide a mechanism to develop new drugs with more precisely targeted effects by activating or inhibiting only the relevant signal transduction pathways. The primary goal of this project is to identify and characterize functionally selective biased ligands for a wide range of GPCRs and to make these available to the scientific community in order to rapidly accelerate and expand the understanding and utility of functional selectivity as a path to new and better medicines. In Specific Aim #1, we will select 12 GPCRs for which a suite of assays will be designed, optimized, and deployed to identify biased ligands against each receptor. The selected GPCRs will be subjected to a robust and validated screening process, through which biased ligands for these GPCRs will be identified. In Specific Aim #2 we will study the selected biased ligands, to improve their bias, potency, and receptor selectivity. This broad scale screening, optimization, and characterization project would dramatically increase the number of potent biased ligands that are available for further study and development, both as research tools and as potential therapeutic candidates. The scientific knowledge resulting from this project has the potential to fundamentally change the way that researchers think about GPCR biology and its role in disease, and to define the way that GPCR ligands themselves are identified, analyzed, and categorized in the future. Functionally selective ligands will be made available to the GPCR community for further investigation of specific GPCR signal transduction pathways. This will dramatically augment understanding and appreciation of functional selectivity by enabling a wide range of in vitro and in vivo experiments. In particular we expect that this project will instigate a rapid advancement in the understanding of functionally selective and nonselective GPCR ligand pharmacology, and enable exploration of the potential for functionally selective molecules to influence pharmacological efficacy, tolerance, and adverse effects of new drug discovery efforts. PUBLIC HEALTH RELEVANCE: Approximately one third of today's FDA-approved drugs act on G-protein coupled receptors (GPCRs), collectively affecting hundreds of millions of people worldwide. In this application, Trevena proposes to demonstrate the broad applicability of functionally selective biased ligands that activate only specific pathways emanating from GPCRs, thus separating the beneficial effects of GPCR activation from the undesirable effects produced by it. The scientific knowledge resulting from this project has the potential to fundamentally change the way that researchers think about GPCR biology and its role in disease, and to redefine the way that GPCR ligands themselves are identified, analyzed, and categorized in the future. This project serves to advance the NIH mission to improve health as it will rapidly accelerate the discovery of a new generation of improved GPCR medicines.