Coordination Funds

协调基金

• 批准号: 290847320
• 负责人: Professorin Dr. Evi Kostenis
• 金额: --
• 依托单位: Institut für Pharmazeutische Biologie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/290847320?language=en
• 关键词: Coordination; Funds

GTP/GDP exchange and the intrinsic GTPase-activity of GTP binding proteins constitute widespread regulatory mechanisms in cells. These are utilized by heterotrimeric αβγ G proteins, downstream effectors of G protein-coupled receptors (GPCRs), to directly or indirectly regulate numerous physiological processes in mammals. Despite the discovery of G proteins almost 30 years ago and their relevance for maintaining homeostasis in response to various extracellular cues, remarkably little effort has been devoted to development of selective and cell permeable pharmacological agents for inhibition of members of this protein family. This is in stark contrast to the plethora of modulators currently available for pharmacological control of GPCRs, and likely relates to the fact that inhibition of receptor function rather than their shared signaling cascades is a more specific approach to interfere with pathologies. Yet, such an approach may fail, if pathology is complex and involves dysregulation of more than one receptor and its associated signaling circuitry as is the case in certain diseases of the lung, in metabolic disturbances, as well as certain forms of pain and cancer. Therefore, development of G protein-targeting pharmacological agents that are active in intact cells, on the level of an isolated organ or ideally also in the living organism would offer unique opportunities to explore the biological consequences that arise from more broad inhibition of signaling components.One such notable G protein inhibiting agent was recently introduced by our RU to the scientific community: FR900359 (FR). FR900359 (FR) is a macrocyclic depsipeptide with exceptional selectivity for inhibition of Gq-mediated signal transduction involving Gαq, Gα11, and Gα14 proteins. It is the core of our current RU2372, and was the only available Gq-specific inhibitor when we formed our consortium. Given its outstanding value as molecular probe to specifically interdict Gq signaling, our current efforts aim at (i) hypothesis-driven design and generation of novel, cell-permeable FR-scaffold-based inhibitors with selectivity for distinct G protein families, (ii) characterization of their mechanism of action including visualization of atomic details of inhibitor-target complexes, and (iii) application of existing and newly developed molecules to understand signaling principles on the level of G protein heterotrimers, their downstream effectors or their upstream activating receptors.We anticipate this strategy to provide us with insight into the relevance and contribution of individual signaling cascades within complex signaling networks in health and disease.

GTP/GDP交换和GTP结合蛋白的内在GTP酶活性构成细胞中广泛的调节机制。它们被异源三聚体αβγ G蛋白（G蛋白偶联受体（GPCR）的下游效应物）利用，直接或间接调节哺乳动物的许多生理过程。尽管近30年前发现了G蛋白，并且它们与响应于各种细胞外信号而维持体内平衡相关，但是用于抑制该蛋白质家族成员的选择性和细胞可渗透的药理学试剂的开发投入非常少。这与目前可用于GPCR的药理学控制的过多调节剂形成鲜明对比，并且可能涉及以下事实：抑制受体功能而不是它们共享的信号传导级联是干扰病理学的更特异性方法。然而，如果病理学是复杂的并且涉及多于一种受体及其相关信号传导回路的失调，如在某些肺部疾病、代谢紊乱以及某些形式的疼痛和癌症中的情况，则这种方法可能失败。因此，开发在完整细胞、离体器官水平或理想情况下也在活生物体中具有活性的G蛋白靶向药物，将为探索更广泛抑制信号传导组分所产生的生物学后果提供独特的机会。最近，我们的RU向科学界介绍了一种这样的G蛋白抑制剂：FR 900359（FR）。FR 900359（FR）是一种大环缩酚肽，对抑制涉及Gαq、Gα11和Gα14蛋白的Gq介导的信号转导具有特殊的选择性。它是我们当前RU 2372的核心，也是我们成立联盟时唯一可用的Gq特异性抑制剂。鉴于其作为特异性阻断Gq信号传导的分子探针的突出价值，我们目前的努力旨在（i）假设驱动的设计和产生对不同G蛋白家族具有选择性的新型的、基于细胞可渗透FR-支架的抑制剂，（ii）表征其作用机制，包括可视化靶标-靶标复合物的原子细节，和（iii）应用现有的和新开发的分子来理解G蛋白异源三聚体水平上的信号原理，它们的下游效应器或它们的上游激活受体。我们期望这种策略为我们提供对个体信号传导的相关性和贡献的洞察力在健康和疾病的复杂信号网络中级联。