An allosteric modulator to control endogenous G protein-coupled receptors with light

Pittolo, Silvia; Gómez‐Santacana, Xavier; Eckelt, Kay; Rovira, Xavier; Dalton, James A. R.; Goudet, Cyril; Pin, Jean‐Philippe; Llobet, Artur; Giraldo, Jesús; Llebaría, Amadeu; Gorostiza, Pau

doi:10.1038/nchembio.1612

Cited by 153 publications

(227 citation statements)

References 30 publications

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“…Importantly, this activity could be switched off using UV illumination to induce cis ‐isomer formation (Figure 3 A; unable to calculate EC 50 ). The extent of photoswitching is similar to that recently reported for an allosteric modulator of the metabotropic glutamate receptor mGluR5, a class C GPCR 12. The effect of PhotoETP on cell viability was determined in islets by using necrosis and apoptosis assays in the dark.…”

supporting

confidence: 76%

“…Although similar “alloswitches” have been described for ionotropic and metabotropic mGluRs,12, 13 this is the first demonstration of their use in a therapeutically relevant class B GPCR. Using a combination of Ca 2+ , cAMP, and insulin assays in CHO‐GLP‐1R and MIN6 cells, as well as islets of Langerhans, we were able to show that PhotoETP allows photoswitching of responses to GLP‐1(7‐36)NH 2 and its less active breakdown product, GLP‐1(9‐36)NH 2 , with similar potency to native BETP.…”

mentioning

confidence: 64%

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Allosteric Optical Control of a Class B G‐Protein‐Coupled Receptor

et al. 2016

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Allosteric regulation promises to open up new therapeutic avenues by increasing drug specificity at G‐protein‐coupled receptors (GPCRs). However, drug discovery efforts are at present hampered by an inability to precisely control the allosteric site. Herein, we describe the design, synthesis, and testing of PhotoETP, a light‐activated positive allosteric modulator of the glucagon‐like peptide‐1 receptor (GLP‐1R), a class B GPCR involved in the maintenance of glucose homeostasis in humans. PhotoETP potentiates Ca2+, cAMP, and insulin responses to glucagon‐like peptide‐1 and its metabolites following illumination of cells with blue light. PhotoETP thus provides a blueprint for the production of small‐molecule class B GPCR allosteric photoswitches, and may represent a useful tool for understanding positive cooperativity at the GLP‐1R.

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confidence: 76%

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confidence: 64%

Allosteric Optical Control of a Class B G‐Protein‐Coupled Receptor

et al. 2016

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“…Importantly, we used these animals at pre-metamorphic stages with most of the organs and neuronal structures being developed and functional. These animals are capable of performing complex behavior trials and show learning abilities and social interactions [21,22,26,27,42,43]. Such features are mostly not established in embryos thus, favoring the tadpole model for experiments estimating effects on human health.…”

Section: Discussionmentioning

confidence: 99%

Automated high-throughput measurement of body movements and cardiac activity of Xenopus tropicalis tadpoles

et al. 2014

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Xenopus tadpoles are an emerging model for developmental, genetic and behavioral studies. A small size, optical accessibility of most of their organs, together with a close genetic and structural relationship to humans make them a convenient experimental model. However, there is only a limited toolset available to measure behavior and organ function of these animals at medium or high-throughput. Herein, we describe an imaging-based platform to quantify body and autonomic movements of Xenopus tropicalis tadpoles of advanced developmental stages. Animals alternate periods of quiescence and locomotor movements and display buccal pumping for oxygen uptake from water and rhythmic cardiac movements. We imaged up to 24 animals in parallel and automatically tracked and quantified their movements by using image analysis software. Animal trajectories, moved distances, activity time, buccal pumping rates and heart beat rates were calculated and used to characterize the effects of test compounds. We evaluated the effects of propranolol and atropine, observing a dose-dependent bradycardia and tachycardia, respectively. This imaging and analysis platform is a simple, cost-effective high-throughput in vivo assay system for genetic, toxicological or pharmacological characterizations.

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“…Similarly, certain chemical series demonstrate "mode switching" whereby small modifications to the structure can result in dramatically changed pharmacological profiles (87). These concerns are particularly relevant when further modifications are applied to the probes, for instance in the generation of irreversible or photoactivatable allosteric molecules (88,89), or through the use of these chemical probes in vivo, where biochemical transformations undertaken by metabolic processes may alter a modulator's potency, cooperativity, receptor selectivity, or mode of action.…”

Section: Chemical Biology Challenges In Designing Allosteric Modulatomentioning

confidence: 99%

Novel Allosteric Modulators of G Protein-coupled Receptors

Gentry

Sexton

Christopoulos

2015

Journal of Biological Chemistry

179

162

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G protein-coupled receptors (GPCRs) are allosteric proteins, because their signal transduction relies on interactions between topographically distinct, yet conformationally linked, domains. Much of the focus on GPCR allostery in the new millennium, however, has been on modes of targeting GPCR allosteric sites with chemical probes due to the potential for novel therapeutics. It is now apparent that some GPCRs possess more than one targetable allosteric site, in addition to a growing list of putative endogenous modulators. Advances in structural biology are also shedding new insights into mechanisms of allostery, although the complexities of candidate allosteric drugs necessitate rigorous biological characterization.

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An allosteric modulator to control endogenous G protein-coupled receptors with light

Cited by 153 publications

References 30 publications

Allosteric Optical Control of a Class B G‐Protein‐Coupled Receptor

Allosteric Optical Control of a Class B G‐Protein‐Coupled Receptor

Automated high-throughput measurement of body movements and cardiac activity of Xenopus tropicalis tadpoles

Novel Allosteric Modulators of G Protein-coupled Receptors

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