药学学报

Name	Target	Pathway and feature
S Ⅱ	AT₁R (angiotensin Ⅱ type 1 receptor)	β-Arrestin; improves myocardial function and protects myocardium^[50]
TRV120023	AT₁R	β-Arrestin; inhibits myocardial hypertrophy while maintaining myofilament
		activity to enhance cardiac contractility^[51]
TRV120026	AT₁R	β-Arrestin; lowers blood pressure and increases cardiac contractility^[39]
TRV120027	AT₁R	β-Arrestin; promotes myocardial contraction and improves cardiovascular
		blood pump^[52]
Ang-(1-7)	AT₁R	β-Arrestin; reduces cardiac weight, ventricular wall thickness, diastolic
		pressure and relieves cardiac hypertrophy^[53]
Aripiprazole	D₂R (dopamine D2 receptor)	β-Arrestin; inhibits elevation of pituitary prolactin induced by dopamine
		agonists and stabilizes dopamine system^[54]
UNC9994A (94A)	D₂R	β-Arrestin; simultaneous targets excessive striatum and absent cortical
		dopamine conduction pathway^[55]
UNC9975A (75A)	D₂R	β-Arrestin; reduces excessive activity, improves recognition and memory
		of new things, reduces conditioned avoidance response^[56]
Carvedilol	βAR (β adrenergic receptor)	β-Arrestin; completely blocks heart lesion caused by G protein signal^[57],
		protects myocardium^[58]
Alprenolol	βAR	β-Arrestin; protects heart (against catecholamine) and increases cardiac
		contractility^[59]
ICL1-9	β₂-AR	β-Arrestin; stimulates cardiac protective signals and myotropic effects^[60]
JNJ7777120	Histamine H4 receptor	β-Arrestin; lessens inflammatory reaction and relieves cough^[61]
Anticoagulant protease-	PAR1 (protease activated receptor 1)	β-Arrestin; induces endothelial barrier protection and prevents permeability
activated protein C (APC)		and vascular leakage^[62]
Platelet activating factor	PAFR (platelet activating factor	β-Arrestin; enhances the activity of matrix metalloproteinase-2 (MMP-2)^[63]
	receptor)
SR121463	V2 arginine-vasopressin (AVP)-	β-Arrestin; inhibites the TM6 molecular switch and activates the TM7 H8
	receptor	domain^[64]
ApoM⁺HDL-S1P	S1PR₁ (Sphingosine 1-phosphate	β-Arrestin; reduces vascular inflammation^[65]
	receptor-1)
(D-Trp12, Tyr34)-PTH	PTHR (parathyroid hormone receptor)	β-Arrestin; leads to the formation of bone without inducing hypercalcemia^[66]

Name	Target	Pathway and feature
S Ⅱ	AT₁R (angiotensin Ⅱ type 1 receptor)	β-Arrestin; improves myocardial function and protects myocardium^[50]
TRV120023	AT₁R	β-Arrestin; inhibits myocardial hypertrophy while maintaining myofilament
		activity to enhance cardiac contractility^[51]
TRV120026	AT₁R	β-Arrestin; lowers blood pressure and increases cardiac contractility^[39]
TRV120027	AT₁R	β-Arrestin; promotes myocardial contraction and improves cardiovascular
		blood pump^[52]
Ang-(1-7)	AT₁R	β-Arrestin; reduces cardiac weight, ventricular wall thickness, diastolic
		pressure and relieves cardiac hypertrophy^[53]
Aripiprazole	D₂R (dopamine D2 receptor)	β-Arrestin; inhibits elevation of pituitary prolactin induced by dopamine
		agonists and stabilizes dopamine system^[54]
UNC9994A (94A)	D₂R	β-Arrestin; simultaneous targets excessive striatum and absent cortical
		dopamine conduction pathway^[55]
UNC9975A (75A)	D₂R	β-Arrestin; reduces excessive activity, improves recognition and memory
		of new things, reduces conditioned avoidance response^[56]
Carvedilol	βAR (β adrenergic receptor)	β-Arrestin; completely blocks heart lesion caused by G protein signal^[57],
		protects myocardium^[58]
Alprenolol	βAR	β-Arrestin; protects heart (against catecholamine) and increases cardiac
		contractility^[59]
ICL1-9	β₂-AR	β-Arrestin; stimulates cardiac protective signals and myotropic effects^[60]
JNJ7777120	Histamine H4 receptor	β-Arrestin; lessens inflammatory reaction and relieves cough^[61]
Anticoagulant protease-	PAR1 (protease activated receptor 1)	β-Arrestin; induces endothelial barrier protection and prevents permeability
activated protein C (APC)		and vascular leakage^[62]
Platelet activating factor	PAFR (platelet activating factor	β-Arrestin; enhances the activity of matrix metalloproteinase-2 (MMP-2)^[63]
	receptor)
SR121463	V2 arginine-vasopressin (AVP)-	β-Arrestin; inhibites the TM6 molecular switch and activates the TM7 H8
	receptor	domain^[64]
ApoM⁺HDL-S1P	S1PR₁ (Sphingosine 1-phosphate	β-Arrestin; reduces vascular inflammation^[65]
	receptor-1)
(D-Trp12, Tyr34)-PTH	PTHR (parathyroid hormone receptor)	β-Arrestin; leads to the formation of bone without inducing hypercalcemia^[66]

偏向β-抑制蛋白的GPCR信号传导机制及药物研究进展

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殷琳 , 陈熙 , 杨秀颖 ^* , 杜冠华 ^*

药学学报 | 综述 2019,54(1): 66-72

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药学学报 | 综述 2019, 54(1): 66-72

偏向β-抑制蛋白的GPCR信号传导机制及药物研究进展

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殷琳, 陈熙, 杨秀颖^*, 杜冠华^*

作者信息

中国医学科学院、北京协和医学院, 药物研究所药物靶点研究与新药筛选北京市重点实验室, 北京 100050

通讯作者:

*杨秀颖, Tel:86-10-63165313, E-mail:lucia@imm.ac.cn;

杜冠华, Tel:86-10-63165184, E-mail:dugh@imm.ac.cn

Mechanisms of β-arrestin-biased GPCR signal transduction and advances in drug research

Lin YIN, Xi CHEN, Xiu-ying YANG^*, Guan-hua DU^*

Affiliations

Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China

出版时间: 2019-01-12 doi: 10.16438/j.0513-4870.2018-0610

文章导航

摘要

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G蛋白偶联受体（G protein-coupled receptors，GPCR）是一类存在于细胞膜表面的受体超家族。随着对GPCR脱敏调节器β-抑制蛋白（β-arrestin）研究的深入，发现GPCRs激活后不仅能通过G蛋白依赖途径进行信号的传导，也能通过非G蛋白依赖途径，即β-抑制蛋白通路来调节受体内吞和脱敏，甚至启动一波新的信号传导，由此提出"偏向性传导"的概念，即配体激活受体后能够选择性激活相应的信号通路，使信号沿着特定"偏好"的下游通路继续向下传导，并将与受体结合后能引起偏向性激活的配体称为"偏向性配体"。一般认为，偏向性的产生是因为配体与受体结合方式存在差别，包括受体构象的差异、下游信号蛋白结合位点的差异以及信号蛋白自身构象的差异等。本文就偏向β-抑制蛋白的GPCR信号传导机制以及偏向β-抑制蛋白通路的配体类药物研究进展做一简要综述。

关键词

G蛋白偶联受体 / β-抑制蛋白 / 偏向性机制 / 偏向性计算方法 / 偏向性配体药物

Abstract

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G protein-coupled receptors (GPCR) are a class of receptor superfamily that exist on the surface of cell membrane. With the intensive studies on the GPCR desensitization regulator-β-arrestins, it is found that activated GPCR can not only conduct signal transduction through G protein-dependent pathway, but also mediate via non-G protein-dependent pathway. In addition to mediate endocytosis and desensitization, β-arrestins also initiate a new series of signal transduction events. Therefore, the concept of "biased transduction" was put forward:the receptor activated by a specific ligand could selectively activate a specific signaling pathway, leading the signal to be transmitted downstream along a "preferential" pathway. We call the ligand that binds to the receptor and causes biased activation "biased ligand". It is generally believed that the phenomenon of bias results from different binding modes of ligands and receptors, including multiple receptor conformations, diverse sites that downstream signal proteins bind, and signal proteins' own conformations, etc. Here we give a brief review focusing on the mechanisms of β-arrestin-biased GPCR signal transduction and the advances in the drug development on β-arrestin biased ligands.

Key words

G protein-coupled receptor / β-arrestin / mechanism of bias / bias calculation method / biased ligand drug

引用本文

殷琳, 陈熙, 杨秀颖, 杜冠华. 偏向β-抑制蛋白的GPCR信号传导机制及药物研究进展. 药学学报, 2019 , 54 (1) : 66 -72 . DOI: 10.16438/j.0513-4870.2018-0610

Lin YIN, Xi CHEN, Xiu-ying YANG, Guan-hua DU. Mechanisms of β-arrestin-biased GPCR signal transduction and advances in drug research[J]. Acta Pharmaceutica Sinica, 2019 , 54 (1) : 66 -72 . DOI: 10.16438/j.0513-4870.2018-0610

正文

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G蛋白偶联受体(GPCR)是一类具有7次跨膜螺旋(7TM)的膜蛋白超家族, 是迄今为止发现的最大的受体超家族, 广泛参与生殖、生长、发育和感知等多种重要的生命活动^[1], 因而在药物研发中备受关注。截至2017年, 美国FDA批准的所有药物中约有34%的药物靶向GPCR^[2]。传统的受体-配体作用模式认为, 配体与受体结合后能够平衡作用于下游的多种信号通路。但在毒蕈碱样胆碱受体激动剂的实验研究过程中^[3]发现, 某些配体可以诱导受体选择性结合特异的G蛋白亚基, 使胞内信号偏向众多下游通路中的某一通路传导, 这一现象被称为“信号偏向性”, 并把该类具有功能选择性的配体称为“偏向性配体”。“偏向性激动(biased agonism)”一词最早由Jarpe等^[4]提出, 用以描述优先激活受体介导的多条下游通路中一条的现象, 这种优先激活某个或某些下游分子而产生不同生理效应的现象还被称为“功能性选择(functional selectivity)^[5]”、“信号偏向性(biased signaling)”等。后续的研究表明, 这种偏向性不仅体现在选择性结合不同的G蛋白亚基、发挥截然不同的生理功能, 还体现在选择性偏向G蛋白通路或G蛋白非依赖的β-抑制蛋白通路中的一种, 继而转化为受体转运和基因转录程序的差异诱导^[6], 最终导致完全不同的生物学效应。这种偏向某一条信号通路的靶向GPCR的药物设计与优化, 被认为是在最大限度地发挥治疗作用的同时减少不良反应的新策略。

1 β-抑制蛋白种类及分布

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抑制蛋白(arrestins)是最初在视觉系统中发现的一类能与G蛋白偶联受体激酶(G protein-coupled receptor kinases, GRKs)联合作用并触发GPCR脱敏的可溶性胞浆蛋白^[7], 由4种同源蛋白组成, 包括非视觉相关的β-抑制蛋白1 (β-arrestin 1, 也称arrestin 2)、β-抑制蛋白2 (β-arrestin 2, 也称arrestin 3)和两个视觉相关的arrestin 1、arrestin 4组成蛋白质家族, 约45 kDa。β-抑制蛋白一般指β-抑制蛋白1和β-抑制蛋白2两个蛋白。β-抑制蛋白1基因位于第11号染色体(Chr. 11 q13), β-抑制蛋白2基因位于第17号染色体(Chr. 17 p13), 两种β-抑制蛋白的氨基序列同源性可达80%。β-抑制蛋白从氨基端到羧基端的保守结构元件包括氨基端臂、功能域Ⅱ (motif Ⅱ)、磷酸盐传感器、铰链结构域、门环/极性核心以及羧基端臂的几种蛋白-蛋白相互作用基序^[8]。位于羧基端的网格蛋白(clathrin)和衔接蛋白2 (adaptor protein 2, AP2)的结合位点是参与受体内化的结构基础^[9]。β-抑制蛋白在体内各个组织中广泛表达, 在神经、脾、肺组织中表达水平最高^[10]。

2 β-抑制蛋白介导GPCR脱敏、支架运输和信号转导

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非视觉抑制蛋白可与超过800个GPCRs相互作用, 另外还能与其他细胞表面受体、网格蛋白、网格蛋白衔接子AP2及各种信号传导蛋白相互作用^[11]。β-抑制蛋白因调控磷酸化的β-肾上腺素受体脱敏而被首次描述^[12]。两种β-抑制蛋白的体内作用相似, 又相互作用, 广泛参与多种信号过程的调控, 介导在空间和时间上都不同于其在G蛋白信号通路中的生物过程。近来研究表明, β-抑制蛋白不仅在G蛋白依赖的信号通路中充当GPCR脱敏的调节因子, 而且可作为独立的介导受体内吞和信号转导的支架和适配器^[13], 它们将内吞蛋白和多种信号分子募集至受体, 使GPCR连接至各种途径, 直接或间接调控基因转录, 参与细胞增殖等其他重要的生命活动^[14]。β-抑制蛋白的结合力相对较弱, 使这种结合更加动态, 其参与信号调节的程度根据受体、激动剂和细胞类型而显著变化。另外有一些受体还依赖于不同β-抑制蛋白间的协同调节作用^[15]。

最近对GPCR的结构、生理和药理学研究深刻地改变了对GPCR激活和靶向治疗的观点。研究表明, GPCR除利用G蛋白依赖通路外, 还可通过G蛋白非依赖的β-抑制蛋白(β-arrestin)通路在细胞内传递信号^[8], 并具有偏向性。一般认为GPCR介导的β-抑制蛋白转导的信号传导需要GPCR-β-抑制蛋白复合物的形成并将复合物运输至内体^[16]。一些GPCRs还能够以GPCR-G蛋白-β抑制蛋白超级聚合体的方式参与信号调节^[17]。GPCR可以诱导β-抑制蛋白产生多种构象^[18]。β-抑制蛋白可与20种以上的蛋白激酶结合^[18]从而介导功能性信号。其中包括:介导丝裂原活化蛋白激酶(mitogen-activated protein kinases, MAPKs)^[19]、Src激酶^[20]及细胞外信号调节激酶(extracellular signal-regulated kinase, ERK)^[21]等信号通路; 介导核因子-κb (nuclear factor, NF-κb)及Wnts/β-catenin^[22]等转录调控过程; 调控蛋白酶激活受体2 (protease activated receptor 2)介导的趋化作用^[23]; 调控神经激肽1受体(neurokinin 1 receptor, NK1R)介导的P物质抗凋亡作用^[24]等。

有趣的是, β-抑制蛋白的不同亚型与GPCR结合后同样能够引起不同的生理学效应。研究表明, 虽然β-抑制蛋白1和2在N端都有核定位序列, 但只有β-抑制蛋白2在C端有一个核输出序列, 从而解释了两者过表达后在细胞质中均有积聚, 而仅有β-抑制蛋白1在细胞核内积累的核质穿梭差异^[25]。此外, β-抑制蛋白1和2支架连接不同的信号通路。例如, 在1型血管紧张素Ⅱ受体(AT₁R)上观察到, β-抑制蛋白2的siRNA敲除可导致ERK信号减弱; 而β-抑制蛋白1的siRNA敲除则导致ERK信号增强^[26]。此外, β-抑制蛋白2还与可卡因成瘾记忆消除^[27]、2型糖尿病胰岛素抵抗^[28]等紧密相关。

3 偏向β-抑制蛋白的GPCR信号转导机制

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导致GPCR信号偏向性传导的分子机制及抑制蛋白依赖性脱敏与信号传导的细微差别尚不清楚。GPCR激活后其细胞内的结构域磷酸化诱导结构重排, 结合β-抑制蛋白或G蛋白。凭借其脱敏/支架功能的独特组合, β-抑制蛋白是G蛋白与非G蛋白信号之间平衡的关键决定因素。通过GPCR上的变构位点调节β-抑制蛋白功能在概念上是相似的。

3.1 多受体构象(multiple receptor conformations)假说

一般认为, 受体存在多个配体特异性的功能构象, 配体受体结合后调控受体活化状态^[29], 诱导受体发生构象变化进而募集不同的下游信号分子, 起始不同的GPCR信号转导^[30]。大量生物、物理和生化研究表明, GPCR在G蛋白依赖和β-抑制蛋白依赖的信号传导之间具有明显不同的构象^[31]。荧光标记数据表明, β-抑制蛋白配体能诱导生长激素样肽Ghrelin和加压素2型受体(V₂R)形成不同的构象^[32]。另外, 利用化学标记法和¹⁹FNMR对β-抑制蛋白偏向性激动剂卡维地洛的研究发现, 在β₂AR的Lys 263^6.25和Cys 265^6.27的相邻区域存在明显的配体特异性侧链重组, 这可能与偏向的激动剂或功能选择性有关, 并在随后的核磁共振研究中证实了功能不同的配体能够使受体细胞内和/或细胞外区域的局部构象发生重排, β₂AR的ICL3 (intracellular loop 3)和TM7 (transmembrane 7)对β-抑制蛋白配体的反应采用了独特的构象^[33]。利用血管紧张素Ⅱ1型受体的功能偏向性突变体进行分子动力学模拟也表明了Gq蛋白偏向和β-抑制蛋白偏向的受体构象之间的差异^[34]。此外, 利用基于质谱的稳定同位素标记的方法对构象变化及动力学进行研究, 观察到β₂AR存在两种不同的构象重排模式, 一种与经典的激动剂作用模式相一致, 另一种则表现出对特定配体呈现特定的构象重排模式^[35]。以上实验结果均为激活的受体存在多重构象的假说提供了直接的实验证据。

3.2 受体磷酸化“条形码(barcode)”假说

受体磷酸化作为GPCR调控的关键机制, 其不同的磷酸化位点可能是导致偏向性信号传递的机制之一, 并由此提出了受体磷酸化“条形码”假说, 即不同的GRKs在给定的受体上磷酸化不同的位点, 诱导受体结合不同的下游分子构象, 进而导致不同的功能后果^[36]。GRKs是一类丝氨酸-苏氨酸激酶, 有7个异构体: GRK1和7仅存在于视觉系统; GRK4主要在生殖道中表达; GRK2、GRK3、GRK5和GRK6在体内普遍表达^[37]。大量的证据表明, 虽然GRK的7个异构体的磷酸化靶位点有很大的重叠, 但也有明显的差异: β₂AR的细胞质尾部与GRK2和/或GRK6的相互作用, 产生不同的磷酸化“条形码”, 表现为不同配体可启动不同的磷酸化模式^[38]。另有实验证明, 以β₂AR为模型, 利用MS技术破译β₂AR上由不同配体(异丙肾上腺素和卡维地洛)诱导的和单独GRKs磷酸化的“条形码”, 发现这些“条形码”与β-抑制蛋白介导的特定功能结果相关^[39]: GRK2的位点(Ser³⁵⁵和Ser³⁵⁶)促进β₂AR内化; GRK6位点(Thr³⁶⁰、Ser³⁶⁴、Ser³⁹⁶、Ser⁴⁰¹、Ser⁴⁰⁷和Ser⁴¹¹)主要负责β-抑制蛋白介导的ERK激活; GRK2和GRK6共同介导受体脱敏^[40]。因此, 靶向GRKs也是寻找β-抑制蛋白偏向性药物的一种策略^[41]。

3.3 β-抑制蛋白构象变化(conformational changes of β-arrestin)

研究发现, β-抑制蛋白的磷酸结合凹面可通过读取不同的磷酸化条形码, 继而转化为特殊的β-抑制蛋白构象, 而这些构象与其功能和信号有明显的偶合作用, 进而导致不同的下游效应^[42]。此外, 用β-抑制蛋白与磷酸肽构建复合物模拟C端尾磷酸化的V2加压素受体(V2 vasopressin receptor, V2Rpp), 通过有限的蛋白质水解和质谱分析, 发现V2Rpp结合并激活β-抑制蛋白1和2, 使先前隐蔽的位点Arg393 (β-抑制蛋白1)或Arg394 (β-抑制蛋白2)暴露, 引起C末端的释放, 增加了β-抑制蛋白1和2的残基371和379之间clathrin结合位点的可及性, 导致β-抑制蛋白1和2与clathrin的结合增强^[43]。另有研究证明, 抑制蛋白和磷酸化激活的受体之间形成高亲和力复合物的机制是一个“两步”过程^[44], 涉及两个不同的结合位点, 即磷酸化识别的N区域, 以及与激活受体高亲和力结合的N-C区域。根据这个模型, 抑制蛋白首先与受体上的磷酸化位点相互作用, 导致负责稳定抑制蛋白非活跃构象的C端结构被释放, 然后经历了构象变化, 暴露了参与高亲和力识别的结构元素^[45]。这些结果提供了β-抑制蛋白从其基础不活跃构象向其生物活性构象转变的直接证据。

总之, β-抑制蛋白偏向的配体与GPCR结合并诱导一个特定的受体构象。这种构象被一个或多个特定的GRKs识别, 并在受体细胞内C末端形成一个独特的磷酸化条形码。随后该条形码被招募的β-抑制蛋白读取, 继而引起β-抑制蛋白的特定构象变化, 最后导致特定蛋白质形成细胞内β-抑制蛋白介导的信号网络(图 1)。

4 信号偏向性传导的研究计算方法

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鉴于信号偏向性可能带来的药理学研究及新药研发领域的无限潜能, 偏向性信号传导的研究计算方法值得更深入的关注和研究。早在1983年Black和Leff^[46]就认为, 实验性反应是一系列步骤的产物, 包括激动剂占据受体、激动剂对系统的作用, 以及产生反应的系统对激动剂的处理。并由此提出了Black/Leff操作模型, 用以测量激动剂的相对有效性。该模型仅适用于对激动剂激动效能的相对大小的量化, 不能直接用于信号偏向性的计算。

随后Kenakin^[47]以Black/Leff操作模型为基础, 提出了用传导系数log(τ/K_A)来计算配体的偏向性。值得注意的是, log(τ/K_A)是系统依赖的, 因此不适用于直接比较配体在两信号途径中的偏向性的大小。为了消除系统差异, 同时比较配体在不同通路中的响应, 研究者们又对log(τ/K_A)值进行了标准化:即以内源性配体为标准, 得到Δlog(τ/K_A)=log(τ/K_A)_药物-log(τ/K_A)_标准。再利用标准化后的Δlog(τ/K_A)值, 可以直接比较试验药物在两种信号途径之间的偏向性大小。此外, ΔΔlog(τ/K_A)=Δlog(τ/K_A)_A-Δlog(τ/K_A)_B可适用于比较两种配体药物A和B引起两条信号途径中的一条应答的偏向性大小。需要明确的是, 由于偏向是一个向量, 减法的顺序很重要, 最直观的方法是确定一种药物对另一种药物的反应效率有多高, 以保证ΔΔlog(τ/K_A)的正性。

此外, Nivedha等^[48]提出了一种计算配体偏向性的新方法:假设从GPCR胞外区域穿过配体结合位点的残基到GPCRs胞内偶联G-蛋白和β-抑制蛋白的界面上残基的能力与配体势及其偶联效能有关, 利用分子动力学(molecular dynamics, MD)轨迹分析受体胞外表面的残基与G蛋白或β-抑制蛋白偶联界面上的残基之间的相关运动, 计算每个激动剂-GPCR复合物到G-蛋白和β-抑制蛋白偶联界面的强度之比, 则待测配体偏向值为: β=PR_lig/PR_ref-1 (PR_lig表示给出的激动剂-受体到β-抑制蛋白界面与到G-蛋白偶联界面的强度之比; PR_ref表示对参考激动剂而言)。该种信号偏向性的计算方法适用于偏向性配体药物的发现, 但其是否真的存在偏向性并能否引起差异性生物学效应, 还要通过实验验证并结合Kenakin^[47]提出的计算模型加以佐证。尽管如此, 该计算方法的优势之处至少包括以下两个方面: ①从虚拟筛选中快速识别有偏向的激动剂, 实现低成本、高通量的效果; ②利用功能活性热区的关键氨基酸残基作为靶配体偏向性优化的起点, 实现针对性优化的功能。

5 偏向β-抑制蛋白信号通路的靶向GPCR药物研究现状

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因为β-抑制蛋白分布广泛且具有多种功能^[49], 配体偏倚提供了组织选择性, 也为GPCR配体类药物的临床用药带来了很好的应用前景, 使得细胞功能的调控和疾病的治疗更具有针对性, 因此偏向β-抑制蛋白信号的配体药物成为研发热点。另外, 也可通过抑制β-抑制蛋白的作用, 减少其激活带来的不良影响。现有研究表明, 该类配体药物的治疗优势主要表现为对心血管系统的保护作用、中枢神经系统相关疾病的治疗作用以及对炎症的调控作用(表 1)^{[39, 50-66]}。

然而, 基于偏向性理论开发药物面临着若干的挑战, 主要表现在体外偏向转化为体内偏向之间的“翻译缺口”, 即信号的偏向可以很容易地在不同信号通路分离的实验系统中被观察和量化, 而体外鉴定存在偏向性的配体在体内可能不会自动产生期望的、有针对性的偏向性信号^[67]。此外, 偏向性定量分析技术和合适筛选方法的开发等技术性难题也是制约偏向性配体应用于实际药理学研究的重要因素。

6 小结与展望

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现已明确, β-抑制蛋白是细胞内复杂信号网络的一大重要的交叉点, 而基于GPCR的G蛋白信号或β-抑制蛋白信号的选择性激活使得有益的生物学效应与无关的毒副作用的分离成为可能。值得注意的是, 独特的受体活性状态可以与不同的细胞背景相互作用, 继而产生(与体外预测的)完全不同的整体信号, 因此迫切需要更为科学和准确的研究方法应用于将体外显示有偏向的信号转换到体内系统的“翻译”计算中, 从而利用配体的偏向性“扬长避短”, 激动可产生或提高疗效的信号, 抑制产生不良反应的信号, 以期开发出高疗效、低毒性的新型靶向GPCR药物, 相信通过对偏向性配体类药物设计与研究的逐渐深入, 会造就一个全新的靶向GPCR新药研发时代。

基金

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国家自然科学基金资助项目(81470159)
国家自然科学基金资助项目(81770847)
中国医学科学院创新工程重大协同创新项目(2016-I2M-3-007)
中国医学科学院创新工程重大协同创新项目(2017-I2M-1-010)

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2019年第54卷第1期

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doi: 10.16438/j.0513-4870.2018-0610

接收时间：2018-07-03
首发时间：2026-01-26
出版时间：2019-01-12

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收稿日期：2018-07-03
修回日期：2018-09-24

基金

国家自然科学基金资助项目(81470159)

国家自然科学基金资助项目(81770847)

中国医学科学院创新工程重大协同创新项目(2016-I2M-3-007)

中国医学科学院创新工程重大协同创新项目(2017-I2M-1-010)

作者信息

中国医学科学院、北京协和医学院, 药物研究所药物靶点研究与新药筛选北京市重点实验室, 北京 100050

通讯作者:

*杨秀颖, Tel:86-10-63165313, E-mail:lucia@imm.ac.cn;

杜冠华, Tel:86-10-63165184, E-mail:dugh@imm.ac.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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RefWorks
TxT

Name	Target	Pathway and feature
S Ⅱ	AT₁R (angiotensin Ⅱ type 1 receptor)	β-Arrestin; improves myocardial function and protects myocardium^[50]
TRV120023	AT₁R	β-Arrestin; inhibits myocardial hypertrophy while maintaining myofilament
		activity to enhance cardiac contractility^[51]
TRV120026	AT₁R	β-Arrestin; lowers blood pressure and increases cardiac contractility^[39]
TRV120027	AT₁R	β-Arrestin; promotes myocardial contraction and improves cardiovascular
		blood pump^[52]
Ang-(1-7)	AT₁R	β-Arrestin; reduces cardiac weight, ventricular wall thickness, diastolic
		pressure and relieves cardiac hypertrophy^[53]
Aripiprazole	D₂R (dopamine D2 receptor)	β-Arrestin; inhibits elevation of pituitary prolactin induced by dopamine
		agonists and stabilizes dopamine system^[54]
UNC9994A (94A)	D₂R	β-Arrestin; simultaneous targets excessive striatum and absent cortical
		dopamine conduction pathway^[55]
UNC9975A (75A)	D₂R	β-Arrestin; reduces excessive activity, improves recognition and memory
		of new things, reduces conditioned avoidance response^[56]
Carvedilol	βAR (β adrenergic receptor)	β-Arrestin; completely blocks heart lesion caused by G protein signal^[57],
		protects myocardium^[58]
Alprenolol	βAR	β-Arrestin; protects heart (against catecholamine) and increases cardiac
		contractility^[59]
ICL1-9	β₂-AR	β-Arrestin; stimulates cardiac protective signals and myotropic effects^[60]
JNJ7777120	Histamine H4 receptor	β-Arrestin; lessens inflammatory reaction and relieves cough^[61]
Anticoagulant protease-	PAR1 (protease activated receptor 1)	β-Arrestin; induces endothelial barrier protection and prevents permeability
activated protein C (APC)		and vascular leakage^[62]
Platelet activating factor	PAFR (platelet activating factor	β-Arrestin; enhances the activity of matrix metalloproteinase-2 (MMP-2)^[63]
	receptor)
SR121463	V2 arginine-vasopressin (AVP)-	β-Arrestin; inhibites the TM6 molecular switch and activates the TM7 H8
	receptor	domain^[64]
ApoM⁺HDL-S1P	S1PR₁ (Sphingosine 1-phosphate	β-Arrestin; reduces vascular inflammation^[65]
	receptor-1)
(D-Trp12, Tyr34)-PTH	PTHR (parathyroid hormone receptor)	β-Arrestin; leads to the formation of bone without inducing hypercalcemia^[66]

Name

Target

Pathway and feature

S Ⅱ

AT₁R (angiotensin Ⅱ type 1 receptor)

β-Arrestin; improves myocardial function and protects myocardium^[50]

TRV120023

AT₁R

β-Arrestin; inhibits myocardial hypertrophy while maintaining myofilament

activity to enhance cardiac contractility^[51]

TRV120026

AT₁R

β-Arrestin; lowers blood pressure and increases cardiac contractility^[39]

TRV120027

AT₁R

β-Arrestin; promotes myocardial contraction and improves cardiovascular

blood pump^[52]

Ang-(1-7)

AT₁R

β-Arrestin; reduces cardiac weight, ventricular wall thickness, diastolic

pressure and relieves cardiac hypertrophy^[53]

Aripiprazole

D₂R (dopamine D2 receptor)

β-Arrestin; inhibits elevation of pituitary prolactin induced by dopamine

agonists and stabilizes dopamine system^[54]

UNC9994A (94A)

D₂R

β-Arrestin; simultaneous targets excessive striatum and absent cortical

dopamine conduction pathway^[55]

UNC9975A (75A)

D₂R

β-Arrestin; reduces excessive activity, improves recognition and memory

of new things, reduces conditioned avoidance response^[56]

Carvedilol

βAR (β adrenergic receptor)

β-Arrestin; completely blocks heart lesion caused by G protein signal^[57],

protects myocardium^[58]

Alprenolol

βAR

β-Arrestin; protects heart (against catecholamine) and increases cardiac

contractility^[59]

ICL1-9

β₂-AR

β-Arrestin; stimulates cardiac protective signals and myotropic effects^[60]

JNJ7777120

Histamine H4 receptor

β-Arrestin; lessens inflammatory reaction and relieves cough^[61]

Anticoagulant protease-

PAR1 (protease activated receptor 1)

β-Arrestin; induces endothelial barrier protection and prevents permeability

activated protein C (APC)

and vascular leakage^[62]

Platelet activating factor

PAFR (platelet activating factor

β-Arrestin; enhances the activity of matrix metalloproteinase-2 (MMP-2)^[63]

receptor)

SR121463

V2 arginine-vasopressin (AVP)-

β-Arrestin; inhibites the TM6 molecular switch and activates the TM7 H8

receptor

domain^[64]

ApoM⁺HDL-S1P

S1PR₁ (Sphingosine 1-phosphate

β-Arrestin; reduces vascular inflammation^[65]

receptor-1)

(D-Trp12, Tyr34)-PTH

PTHR (parathyroid hormone receptor)

β-Arrestin; leads to the formation of bone without inducing hypercalcemia^[66]