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首页> 外文期刊>Biochemical Pharmacology >Angiotensin II cyclic analogs as tools to investigate AT(1)R biased signaling mechanisms
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Angiotensin II cyclic analogs as tools to investigate AT(1)R biased signaling mechanisms

机译：血管紧张素II环状类似物作为研究（1）R偏置信号机制的工具

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摘要

G protein coupled receptors (GPCRs) produce pleiotropic effects by their capacity to engage numerous signaling pathways once activated. Functional selectivity (also called biased signaling), where specific compounds can bring GPCRs to adopt conformations that enable selective receptor coupling to distinct signaling pathways, continues to be significantly investigated. However, an important but often overlooked aspect of functional selectivity is the capability of ligands such as angiotensin II (AngII) to adopt specific conformations that may preferentially bind to selective GPCRs structures. Understanding both receptor and ligand conformation is of the utmost importance for the design of new drugs targeting GPCRs. In this study, we examined the properties of AngII cyclic analogs to impart biased agonism on the angiotensin type 1 receptor (AT(1)R). Positions 3 and 5 of AngII were substituted for cysteine and homocysteine residues ([Sar(1)Hcy(3,5)]AngII, [Sar(1)Cys(3)Hcy(5)]AngII and [Sar(1)Cys(3,5)]AngII) and the resulting analogs were evaluated for their capacity to activate the Gq/11, G12, Gi2, Gi3, Gz, ERK and beta-arrestin (beta arr) signaling pathways via AT(1)R. Interestingly, [Sar(1)Hcy(3.5)]AngII exhibited potency and full efficacy on all pathways tested with the exception of the Gq pathway. Molecular dynamic simulations showed that the energy barrier associated with the insertion of residue Phe(8) of AngII within the hydrophobic core of AT(1)R, associated with Gq/11 activation, is increased with [Sar(1)Hcy(3,5)]AngII. These results suggest that constraining the movements of molecular determinants within a given ligand by introducing cyclic structures may lead to the generation of novel ligands providing more efficient biased agonism.
机译：G蛋白偶联受体（GPCR）通过其活化后通过其接合许多信号传导途径产生脂肪熵效应。功能选择性（也称为偏置信号传导），其中特异性化合物可以使GPCR用于采用使能选择性受体耦合与不同信号通路的构象，继续显着研究。然而，功能选择性的重要但经常被忽视的方面是配体如血管紧张素II（Angii）的能力，以采用可以优先结合选择性GPCR结构的具体构象。理解受体和配体构造对于针对GPCR的新药设计至关重要。在这项研究中，我们检查了血管素循环类似物的性质，以赋予血管紧张素1型受体（在（1）R）上的偏置激动。 Angii的位置3和5被用于半胱氨酸和同型内氨酸残基（[SAR（1）Hcy（3,5）] Angii，[SAR（1）Cys（3）Hcy（5）] Angii和[Sar（1）Cys （3,5）] Angii）和所得类似物的能力以在（1）R通过（1）R激活GQ / 11，G12，GI2，GI3，GZ，ERK和BETA-ARRECTIN（BETA ARR）信号传导途径的能力。有趣的是，[SAR（1）Hcy（3.5）] Angii表现出对除GQ途径除外所有途径的效力和全部疗效。分子动态模拟显示与在（1）R激活的（1）Hcy相关的（1）R的疏水核中插入与（1）R的疏水核心内的残留物（8）相关的能量屏障增加[SAR（1）Hcy（3， 5）] Angii。这些结果表明，通过引入环状结构来限制给定配体内的分子决定簇的运动可能导致产生更有效的偏置激动的新型配体的产生。

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