GPCRs are inherently flexible molecules existing in an equilibrium of multiple conformations. Binding of GPCR agonists shifts this equilibrium. Certain agonists can increase the fraction of active-like conformations that predispose the receptor to coupling to a particular signal transducer or a select group of transducers. Such agonists are called biased, in contrast to balanced agonists that facilitate signaling via all transducers the receptor couples to. These biased agonists preferentially channel the signaling of a GPCR to particular G proteins, GRKs, or arrestins. Preferential activation of particular G protein or arrestin subtypes can be beneficial, as it would reduce unwanted on-target side effects, widening the therapeutic window. However, biasing GPCRs has two important limitations: a) complete bias is impossible due to inherent flexibility of GPCRs; b) receptor-independent functions of signal transducer proteins cannot be directly affected by GPCR ligands or differential receptor barcoding by GRK phosphorylation. This article is part of the Special Issue on "Ligand Bias".

2024-07-01·Cellular signalling

Computational modelling of dynamic cAMP responses to GPCR agonists for exploration of GLP-1R ligand effects in pancreatic β-cells and neurons

Article

作者: Bridge, Lloyd ; Chen, Shiqian ; Jones, Ben

The glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor (GPCR) which plays important physiological roles in insulin release and promoting fullness. GLP-1R agonists initiate cellular responses by cyclic AMP (cAMP) pathway signal transduction. Understanding of the potential of GLP-1R agonists in the treatment of type 2 diabetes may be advanced by considering the cAMP dynamics for agonists at GLP-1R in both pancreatic β-cells (important in insulin release) and neurons (important in appetite regulation). Receptor desensitisation in the cAMP pathway is known to be an important regulatory mechanism, with different ligands differentially promoting G protein activation and desensitisation. Here, we use mathematical modelling to quantify and understand experimentally obtained cAMP timecourses for two GLP-1R agonists, exendin-F1 (ExF1) and exendin-D3 (ExD3), which give markedly different signals in β-cells and neurons. We formulate an ordinary differential equation (ODE) model for the dynamics of cAMP signalling in response to G protein-coupled receptor (GPCR) ligands, encompassing ligand binding, receptor activation, G protein activation, desensitisation and second messenger generation. We validate our model initially by fitting to timecourse data for HEK293 cells, then proceed to parameterise the model for β-cells and neurons. Through numerical simulation and sensitivity studies, our analysis adds support to the hypothesis that ExF1 offers more potential glucose regulation benefit than ExD3 over long timescales via signalling in pancreatic β-cells, but that there is little difference between the two ligands in the potential appetite suppression effects offered via long-time signalling in neurons on the same timescales.

2024-04-30·Proceedings of the National Academy of Sciences of the United States of America

Single-chain fluorescent integrators for mapping G-protein-coupled receptor agonists

Article

作者: Li, Xingyu ; Wang, Wenjing ; Sescil, Jennifer ; Kroning, Kayla ; Wilson, Avery ; Shen, Jiaqi ; Gannot, Noam ; Zhou, Guanwei ; Putansu, Aubrey ; Fiel, Hailey ; Li, Peng

G protein-coupled receptors (GPCRs) transduce the effects of many neuromodulators including dopamine, serotonin, epinephrine, acetylcholine, and opioids. The localization of synthetic or endogenous GPCR agonists impacts their action on specific neuronal pathways. In this paper, we show a series of single-protein chain integrator sensors that are highly modular and could potentially be used to determine GPCR agonist localization across the brain. We previously engineered integrator sensors for the mu- and kappa-opioid receptor agonists called M- and K-Single-chain Protein-based Opioid Transmission Indicator Tool (SPOTIT), respectively. Here, we engineered red versions of the SPOTIT sensors for multiplexed imaging of GPCR agonists. We also modified SPOTIT to create an integrator sensor design platform called SPOTIT for all GPCRs (SPOTall). We used the SPOTall platform to engineer sensors for the beta 2-adrenergic receptor (B2AR), the dopamine receptor D1, and the cholinergic receptor muscarinic 2 agonists. Finally, we demonstrated the application of M-SPOTIT and B2AR-SPOTall in detecting exogenously administered morphine, isoproterenol, and epinephrine in the mouse brain via locally injected viruses. The SPOTIT and SPOTall sensor design platform has the potential for unbiased agonist detection of many synthetic and endogenous neuromodulators across the brain.

项与 GPCR agonist(4e Therapeutics, Inc.) 相关的新闻（医药）

2024-06-12

·生物制药小编

一个临床失败，放弃眼科赛道

近日，Skye Bioscience公司宣布，其用于青光眼和高眼压患者的眼科乳剂SBI-100 OE的Ⅱa期临床试验未达到降低眼压的主要终点，公司计划停止及SBI-100 OE的全部研发工作。这个失败的临床结果似乎成为了公司彻底转变战略方向的一个契机，除了SBI-100 OE之外，公司还将放弃开发SBI-100在内的所有眼科管线，并集中资源全力开发其代谢项目，以将公司运营跑道延长至2027年。甩掉眼科包袱？ SBI-100是一种合成的四氢大麻酚前药，可以穿过角膜转化为四氢大麻酚（THC），进而结合和激活关键眼组织中的人源大麻素受体（CB1），用于降低青光眼和高眼压患者的眼压升高。SBI-100 OE是Skye 采用特有的纳米乳剂配制成滴眼液，旨在实现局部递送并提高其在眼组织中的生物利用度。该项试验是一项双盲、随机、安慰剂对照临床试验，旨在评估两种浓度的SBI-100 OE（1.0%或0.5%）与安慰剂对比的疗效和安全性，该试验每天给药两次，持续14 天。试验主要终点是评估SBI-100 OE组与安慰剂组的日眼压变化。结果显示，与安慰剂相比，SBI-100 OE组患者的的IOP并没有取得统计学上的显著改善。安全性方面，没有患者因不良事件而停药。对于这款在2023年还是公司核心支柱管线，市场的反应并没有想象中剧烈。Skye股价仅下跌了8.8%。这主要原因在于公司在去年将研发方向转向了十分火热的减肥赛道，极大的对冲了这个临床失败可能对公司造成的打击。2023年8月，Skye以2000万美元收购锐意生物（目前更名为Bird Rock Bio），获得了其核心管线Nimacimab-一款阻断CB1的抗体药，处于临床II期开发阶段。在完成对Bird Rock收购的当天，Skye还宣布完成1700万美元融资，公司当时对笔融资的使用预计是维持公司运营至2024年，可见，公司的现金流对于后续推动两个管线的临床开发是比较紧张的。这笔收购对于如今已经遭遇失败的Skye而言，是相当未雨绸缪的一笔投资。这笔收购不仅大幅提升了公司股价，还带来了投资，公司的现金流状况得到大大好转。多亏了这笔收购得益于减肥药火热，Skye的现状很快有了好转，今年以来，Skye的股价上涨了超400%，且在今年一季度，Skye还成功完成了两次大额融资（5025万美元、4000万美元）。随着股价上涨，公司也顺利将公司股票从OTC（场外交易市场）转板至纳斯达克交易市场。 CB1是人类中枢神经系统中表达量最高的G蛋白偶联受体(GPCR)之一，主要存在于大脑，在脾脏、肺、胸腺、心脏和血管中也有表达。由组织分布的多样性，CB1参与许多重要的生理病理过程，CB1作为疼痛、炎症、肥胖以及药物滥用等多个疾病领域药物的重要开发靶点。 2006年，首个CB1拮抗利Rimonabant获得了欧洲药监局的上市批准，用于肥胖症的治疗，然而Rimonabant因为会显著增加引发焦虑、抑郁、自杀倾向等多种精神方面的副作用风险而被禁止使用，2009年被EMA退市下架。此后，默沙东、辉瑞等药企也放弃CB1管线的开发。作为一款抗体药，小分子CB1抑制剂最明显的优势在于，Nimacimab不易穿过血脑屏障，引起因靶向CB1而造成的中枢神经系统副作用风险更低。Nimacimab的I期临床试验显示，其对认知功能不会产生影响，也未造成精神疾病风险增加，在高效抑制CB1信号传导的同时，不会对中枢神经系统造成潜在影响。诺和诺德也涉足了这个靶点，去年8月，诺和诺德10.75亿美元收购Inversago公司，获得了其首发管线INV-202--一种用于治疗肥胖、糖尿病等代谢疾病的口服CB1抑制剂。总结 CB1近两年因减肥赛道火热而重获关注，Skye也算是加入的较早一批企业，不过，如今减肥领域的布局者愈多，竞争异常激烈，未来Skye能不能跑不出来不知道，但是如果没有对Bird Rock的这笔收购，或许公司的倒闭离这次SBI-100 OE的宣告失败将会不远。参考出处 https://ir.skyebioscience.com/news-events/press-releases/detail/197/skye-concentrates-strategy-and-clinical-development-focus https://d1io3yog0oux5.cloudfront.net/_6dfc7ee9d4b21b8379f916a440404d04/skyebioscience/db/781/7011/pdf/240601_SKYE_Investor+Presentation.pdf GPCR靶点抗体：大麻素受体CB的抗体开发

并购临床2期临床终止

100 项与 GPCR agonist(4e Therapeutics, Inc.) 相关的药物交易

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