Biased agonism: An emerging paradigm in GPCR drug discovery.
Biased agonism: An emerging paradigm in GPCR drug discovery.
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DOI：
10.1016/j.bmcl.2015.12.024
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发表时间：
2016-01-15
影响因子：
2.7
通讯作者：
Bohn LM
中科院分区：
文献类型：
--
作者：
Rankovic Z;Brust TF;Bohn LM
G蛋白偶联受体在历史上一直是最可药物化的细胞蛋白类之一。这个大型受体基因家族的成员与主要效应物G蛋白偶联，G蛋白具有再生和信号放大的机制，受体和配体的每次接合本身就是一个动力学事件。近年来，已经发现GPCR与抑制蛋白相互作用以在不存在G蛋白相互作用的情况下启动信号传播。这一巅峰观察改变了以前对GPCR功效线性谱的概念，并揭示了GPCR研究和药物发现的新范式，该范式依赖于GPCR信号的多维性。配体被发现选择性地赋予一种途径的活性超过另一种途径，这种现象被称为“偏向激动”或“功能选择性”。虽然近年来对这种现象的理解取得了很大的进步，但两个关键问题仍然主导着该领域：我们如何合理地设计有偏见的GPCR配体，以及最终，哪些生理反应是由于G蛋白与抑制蛋白的相互作用。本次审查将讨论目前的理解偏信号的一些关键方面，这些问题有关，包括偏信号的性质和测量配体偏差的方法，以及药物发现应用和药物化学策略，突出在这个快速发展的领域的挑战和机遇的相关例子的机械见解。
G protein coupled receptors have historically been one of the most druggable classes of cellular proteins. The members of this large receptor gene family couple to primary effectors, G proteins, that have built in mechanisms for regeneration and amplification of signaling with each engagement of receptor and ligand, a kinetic event in itself. In recent years GPCRs, have been found to interact with arrestin proteins to initiate signal propagation in the absence of G protein interactions. This pinnacle observation has changed a previously held notion of the linear spectrum of GPCR efficacy and uncovered a new paradigm in GPCR research and drug discovery that relies on multidimensionality of GPCR signaling. Ligands were found that selectively confer activity in one pathway over another, and this phenomenon has been referred to as ‘biased agonism’ or ‘functional selectivity’. While great strides in the understanding of this phenomenon have been made in recent years, two critical questions still dominate the field: How can we rationally design biased GPCR ligands, and ultimately, which physiological responses are due to G protein versus arrestin interactions? This review will discuss the current understanding of some of the key aspects of biased signaling that are related to these questions, including mechanistic insights in the nature of biased signaling and methods for measuring ligand bias, as well as relevant examples of drug discovery applications and medicinal chemistry strategies that highlight the challenges and opportunities in this rapidly evolving field.
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DOI：
10.1073/pnas.84.24.8879
发表时间：
1987-12-01
影响因子：
11.1
作者：
BENOVIC, JL;KUHN, H;LEFKOWITZ, RJ
通讯作者：
LEFKOWITZ, RJ
DOI：
10.1124/jpet.114.220293
发表时间：
2015-03-01
影响因子：
3.5
作者：
Brust, Tarsis F.;Hayes, Michael P.;Watts, Val J.
通讯作者：
Watts, Val J.
影响因子：
2.9
作者：
Gavériaux-Ruff, C;Kieffer, BL
通讯作者：
Kieffer, BL
影响因子：
3.6
作者：
Gay, EA;Urban, JD;Mailman, RB
通讯作者：
Mailman, RB
影响因子：
64.8
作者：
Goodman, OB;Krupnick, JG;Benovic, JL
通讯作者：
Benovic, JL