Selective modulation of GPCR signal transduction with biased ligands

使用偏向配体选择性调节 GPCR 信号转导

• 批准号: 7942893
• 负责人: MICHAEL William LARK
• 金额: $ 342.56万
• 依托单位: TREVENA, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7942893
• 关键词: Adrenergic Agents; Adrenergic beta-Antagonists; Adverse effects; Affect; Agonist; Analgesics; Applications Grants; Biochemical; Biological; Biological Assay; Biology; Chemistry; Commit; Communities; Development; Disease; Exhibits; FDA approved; Fostering; Future; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Generations; Goals; Health; Health Benefit; Heterotrimeric GTP-Binding Proteins; In Vitro; Investigation; Ligands; Medicine; Mission; Names; Nociception; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Physiological; Physiology; Process; Public Health; Receptor Activation; Receptor Signaling; Relative (related person); Research; Research Personnel; Role; Screening procedure; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Testing; Therapeutic; Therapeutic Effect; United States National Institutes of Health; base; design; drug discovery; high throughput screening; improved; in vivo; knowledge of results; public health relevance; receptor; research study; response; small molecule; small molecule libraries; tool; tool development

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.

描述（由申请人提供）：当今 FDA 批准的药物中大约有三分之一作用于 G 蛋白偶联受体 (GPCR)，共同影响全世界数亿人。这些药物是基于有限的信号传导范式开发的，通过激动剂刺激受体，导致通过异三聚体 G 蛋白从受体发出的所有细胞内信号传导途径的激活。然而，最近的研究表明，GPCR 不仅以这种简单的方式发出信号，而且还激活由平行信号转导途径组成的下游效应网络。现在提出，与无偏向的分子相比，偏向于诱导或阻断特定信号传导途径的 GPCR 配体将具有差异化的生理学，通​​过选择性地参与所需的信号级联子集来提供一组独特的有益作用，这些作用可以与正位激动剂通常表现出的不良作用。这种功能选择性可能提供一种机制，通过仅激活或抑制相关信号转导途径来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，以便快速加速和扩大对功能选择性的理解和实用性，作为新的和新的途径。更好的药物。在特定目标 #1 中，我们将选择 12 个 GPCR，为其设计、优化和部署一套测定法，以识别针对每种受体的偏向配体。选定的 GPCR 将接受稳健且经过验证的筛选过程，通过该过程将鉴定出这些 GPCR 的有偏差配体。在具体目标#2 中，我们将研究选定的有偏配体，以提高它们的偏倚、效力和受体选择性。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，既可以作为研究工具，也可以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思考方式，并定义未来 GPCR 配体本身的识别、分析和分类的方式。功能选择性配体将提供给 GPCR 界，以进一步研究特定的 GPCR 信号转导途径。通过实现广泛的体外和体内实验，这将极大地增强对功能选择性的理解和欣赏。我们特别期望该项目将促进对功能选择性和非选择性 GPCR 配体药理学的理解的快速进步，并能够探索功能选择性分子影响新药发现工作的药理功效、耐受性和不良反应的潜力。 公共健康相关性：当今 FDA 批准的药物中约有三分之一作用于 G 蛋白偶联受体 (GPCR)，共同影响着全世界数亿人。在本申请中，Trevena 提议证明功能选择性偏向配体的广泛适用性，这些配体仅激活 GPCR 发出的特定途径，从而将 GPCR 激活的有益作用与其产生的不良作用分开。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的作用的思考方式，并重新定义未来 GPCR 配体本身的识别、分析和分类方式。该项目有助于推进 NIH 改善健康的使命，因为它将迅速加速新一代改进 GPCR 药物的发现。