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Translating in vitro ligand bias into in vivo efficacy

机译：将体外配体偏差翻译成体内疗效

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It is increasingly apparent that ligand structure influences both the efficiency with which G protein-coupled receptors (GPCRs) engage their downstream effectors and the manner in which they are activated. Thus, 'biased' agonists, synthetic ligands whose intrinsic efficacy differs from the native ligand, afford a strategy for manipulating GPCR signaling in ways that promote beneficial signals while blocking potentially deleterious ones. Still, there are significant challenges in relating in vitro ligand efficacy, which is typically measured in heterologous expression systems, to the biological response in vivo, where the ligand is acting on natively expressed receptors and in the presence of the endogenous ligand. This is particularly true of arrestin pathway selective 'biased' agonists. The type 1 parathyroid hormone receptor (PTH1R) is a case in point. Parathyroid hormone (PTH) is the principal physiological regulator of calcium homeostasis, and PTH1R expressed on cells of the osteoblast lineage are an established therapeutic target in osteoporosis. In vitro, PTH1R signaling is highly sensitive to ligand structure, and PTH analogs that affect the selectivity/kinetics of G protein coupling or that engage arrestin-dependent signaling mechanisms without activating heterotrimeric G proteins have been identified. In vivo, intermittent administration of conventional PTH analogs accelerates the rate of osteoblastic bone formation, largely through known cAMP-dependent mechanisms. Paradoxically, both intermittent and continuous administration of an arrestin pathway-selective PTH analog, which in vivo would be expected to antagonize endogenous PTH1R-cAMP signaling, also increases bone mass. Transcriptomic analysis of tissue from treated animals suggests that conventional and arrestin pathway-selective PTH1R ligands act in largely different ways, with the latter principally affecting pathways involved in the regulation of cell cycle, survival, and migration/cytoskeletal dyna
机译：越来越明显，配体结构影响G蛋白偶联受体（GPCR）与其下游效应器的效率和它们被激活的方式影响。因此，“偏置”激动剂，其内在功效与天然配体不同的合成配体，提供了一种以促进有益信号的方式操纵GPCR信号的策略，同时阻止潜在的有害的信号。尽管如此，在体外配体疗效方面存在显着挑战，该疗效通常在异源表达系统中测量，在体内的生物反应中，其中配体作用于本地表达的受体并在内源配体的存在下。这尤其如此，对逮捕型途径有选择性的“偏见”激动剂。 1型甲状旁腺激素受体（PTH1R）是一种情况。甲状旁腺激素（PTH）是钙稳态的主要生理调节因子，骨赘的细胞表达PTH1R是骨质疏松症的既定治疗靶标。在体外，PTH1R信号传导对配体结构非常敏感，并且已经鉴定了影响G蛋白偶联的选择性/动力学的第pTH类似物或者在不激活异映上的G蛋白的情况下接合依赖于依赖性信号传导机制。在体内，常规第pTH类似物的间歇施用加速了成骨细胞骨形成的速率，主要是通过已知的营养依赖性机制。矛盾的是，在体内的诱导途径和连续给药的间歇和连续给药预期在体内拮抗内源性Pth1r-camp信号传导，也增加了骨质量。来自治疗动物的组织的转录组织分析表明，常规和抑制型途径选择性PTH1R配体在很大程度上起作用，后者主要影响细胞周期，存活和迁移/细胞骨骼DYNA调节中涉及的途径

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