Selective modulation of GPCR signal transduction with biased ligands

描述(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(GPCRs)，共同影响着全球数亿人。这些药物是基于有限的信号模式开发的，通过激动剂刺激受体，导致通过异源三聚体G蛋白激活受体发出的所有细胞内信号通路。然而，最近的研究表明，GPCRs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通路组成的下游效应网络。现在有人提出，与无偏见的分子相比，偏向于诱导或阻断特定信号通路的GPCR配体将具有不同的生理学，通过选择性地结合所需的信号级联子集来提供一组独特的有益效果，这些效果可以与正畸类激动剂通常表现出的不良效果区分开来。这种功能选择性可能提供了一种机制，通过仅激活或抑制相关的信号转导通路来开发具有更精确靶向作用的新药。该项目的主要目标是为广泛的GPCR确定和表征具有功能选择性的偏向配体，并将其提供给科学界，以便迅速加速和扩大对功能选择性的理解和利用，将其作为获得新的和更好的药物的途径。在具体目标#1中，我们将选择12个GPCR，将针对这些GPCR设计、优化和部署一套分析方法，以识别针对每个受体的偏向配体。选定的GPCRs将接受强有力和有效的筛选程序，通过该程序将确定这些GPCRs的有偏见的配体。在特定的目标#2中，我们将研究选定的偏向配体，以改善它们的偏向、效力和受体的选择性。这一大规模的筛选、优化和表征项目将极大地增加可用于进一步研究和开发的有效偏向配体的数量，无论是作为研究工具还是潜在的治疗候选。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作用的思考方式，并定义未来GPCR配体本身被识别、分析和分类的方式。功能选择性配体将提供给GPCR界，用于进一步研究特定的GPCR信号转导途径。这将极大地增强对功能选择性的理解和欣赏，使广泛的体外和体内实验成为可能。特别是，我们预计该项目将推动对功能选择性和非选择性GPCR配基药理学的理解的快速进步，并使人们能够探索功能选择性分子影响新药发现努力的药理疗效、耐受性和不良反应的可能性。 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(GPCRs)，共同影响着全球数亿人。在这项应用中，Trevena建议证明功能选择性偏向配体的广泛适用性，这些配体只激活GPCRs发出的特定通路，从而将GPCRs激活的有利影响与其产生的不良影响分开。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作用的看法，并在未来重新定义GPCR配体本身被识别、分析和分类的方式。该项目旨在推进美国国立卫生研究院改善健康的使命，因为它将迅速加速发现新一代改进的GPCR药。

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.