Optical Control of Insulin Secretion Using an Incretin Switch

Broichhagen, Johannes; Podewin, Tom; Meyer‐Berg, Helena; Ohlen, Yorrick von; Johnston, Natalie R.; Jones, Ben; Bloom, Stephen R.; Rutter, Guy A.; Hoffmann‐Röder, Anja; Hodson, David J.; Trauner, Dirk

doi:10.1002/anie.201506384

Cited by 86 publications

(89 citation statements)

References 35 publications

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“…Target evaluation:t he photopharmacological approach should always take into consideration localized diseases with targets where the delivery of light is feasible. [120,137] This selectivity towards different functions might under certain circumstances be desirable,b ut often can be problematic.T hus,r esearchers should bear this aspect in mind when transitioning to in vivo experiments. 2.…”

Section: Angewandte Chemiementioning

confidence: 99%

Emerging Targets in Photopharmacology

et al. 2016

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The field of photopharmacology uses molecular photoswitches to establish control over the action of bioactive molecules. It aims to reduce systemic drug toxicity and the emergence of resistance, while achieving unprecedented precision in treatment. By using small molecules, photopharmacology provides a viable alternative to optogenetics. We present here a critical overview of the different pharmacological targets in various organs and a survey of organ systems in the human body that can be addressed in a non-invasive manner. We discuss the prospects for the selective delivery of light to these organs and the specific requirements for light-activatable drugs. We also aim to illustrate the druggability of medicinal targets with recent findings and emphasize where conceptually new approaches have to be explored to provide photopharmacology with future opportunities to bring "smart" molecular design ultimately to the realm of clinical use.

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Section: Angewandte Chemiementioning

confidence: 99%

Emerging Targets in Photopharmacology

et al. 2016

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“…[9][10][11][12][13] Remarkably and surprisingly, GPCRs, next to enzymes the most important drug targets, have only been addressed very recently with photoswitchable tool compounds. Targets have been the metabotropic glutamate receptors, [14,15] the class B glucagon-like peptide-1 receptor, [16,17] the adenosine, the dopamine and μ-opioid receptor, [18][19][20] and the muscarinic acetylcholine receptor. [9] At the same time of the preparation of this manuscript, Westphal et al described photoswitchable THC-derivatives, two of which act as CB 1 R agonists, as shown by coupling with an inwardly-rectifying potassium channel and forskolin-stimulated cAMP production.…”

Section: Introductionmentioning

confidence: 99%

The First Photochromic Affinity Switch for the Human Cannabinoid Receptor 2

Dolles

Straßer

Wittmann

et al. 2018

Advanced Therapeutics

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The hCB 2 R plays an important in the immune system and is centrally expressed in microglia. The hCB 2 R activated by agonists hold great therapeutic potential, e.g., in neuroinflammation. It is currently not yet elucidated how pathophysiological processes are mediated by the hCB 2 R. Here, photochromic affinity switches based on a drugable benzimidazole core through azologization and computational studies are developed. Structure-activity relationships (SARs) lead to compounds with high selectivity over hCB 1 R that can be reversibly switched to a higher affinity cis-form proved on the receptor level by radioligand binding studies and translating into an affinity change in a functional GTPγ S assay. cAMP ELISA and the change in expression level of two genes regulated by CREB proves that the compounds act as partial agonists.agonist SR141716A (rimonabant) had been approved as a drug for obesity in European countries, albeit its putative risk of psychiatric problems led to its suspension from the market in 2008. Far less is known about the hCB 2 R and its role in the healthy, but especially in the diseased human body. It was first recognized as the "peripheral" CBR, [2] since hCB 2 Rs are localized in the immune system and modulate immune cell migration and cytokine release. [3] More recently, it was shown that the hCB 2 R is located in the central nervous system also, mainly expressed in microglial cells.Pronounced overexpression of CB 2 R and fatty acid amide hydrolase is observed in neuroinflammatory processes in the brain and specifically in microglia cells that surround β-amyloid plaques. [4] The expression level correlates well with Aβ 42 -level and plaque formation, although not directly with cognitive status, indicating that pathogenic processes lead to hCB 2 R overexpression. [5] Due to the expression of hCB 2 R in activated microglia and the possibility of reduction of cell activation by hCB 2 R agonists, therapeutic application of such compounds is promising. It was shown in several in vitro-assays that hCB 2 R agonists and partial agonists reduce both the number of activated microglia cells surrounding Aβ plaques and the level of pro-inflammatory cytokines. It is currently not yet elucidated how exactly these effects are mediated by the hCB 2 R, in which sequence (patho)physiologic activation takes place and which time-scale is underlying these processes. [6] Both hCBR subtypes are activated to the same extent by endocannabinoids and classical phytocannabinoids like 9 -THC, [7] which also activates GPR18, GPR55, peroxisome proliferatoractivated receptor gamma nuclear receptor, and Transient Receptor Potential Ankyrin 1 (TRPA1) and Transient Receptor Potential Vannilloid-type 2 (TRPV2) cation channels at >1 µm. [8] In the last years "photopharmacology" has rapidly emerged and found remarkable application for the control of biological functions by light with the unprecedented spatio-temporal solution that was made possible by chemical photoswitches that are incorporated into biologically active molecules...

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“…24 Backbone modification has received relatively little attention as an approach to the design of peptide hormone analogues, but holds significant promise for generation of novel peptides. 22, 24, 26–33 …”

Section: Introductionmentioning

confidence: 99%

Characterization of signal bias at the GLP-1 receptor induced by backbone modification of GLP-1

Hager

Clydesdale

Gellman

et al. 2017

Biochemical Pharmacology

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The glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor that is a major therapeutic target for the treatment of type 2 diabetes. Activation of this receptor promotes insulin secretion and blood glucose regulation. The GLP-1R can initiate signaling through several intracellular pathways upon activation by GLP-1. GLP-1R ligands that preferentially stimulate subsets among the natural signaling pathways (“biased agonists”) could be useful as tools for elucidating the consequences of specific pathways and might engender therapeutic agents with tailored effects. Using HEK-293 cells recombinantly expressing human GLP-1R, we have previously reported that backbone modification of GLP-1, via replacement of selected α-amino acid residues with β-amino acid residues, generates GLP-1 analogues with distinctive preferences for promoting G protein activation versus β-arrestin recruitment. Here, we have explored the influence of cell background across these two parameters and expanded our analysis to include affinity and other key signaling pathways (intracellular calcium mobilization and ERK phosphorylation) using recombinant human GLP-1R expressed in a CHO cell background, which has been used extensively to demonstrate biased agonism of GLP-1R ligands. The new data indicate that α/β-peptide analogues of GLP-1 exhibit a range of distinct bias profiles relative to GLP-1 and that broad assessment of signaling endpoints is required to reveal the spectrum of behavior of modified peptides. These results support the view that backbone modification via α→β amino acid replacement can enable rapid discovery of peptide hormone analogues that display substantial signal bias at a cognate GPCR.

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Optical Control of Insulin Secretion Using an Incretin Switch

Cited by 86 publications

References 35 publications

Emerging Targets in Photopharmacology

Emerging Targets in Photopharmacology

The First Photochromic Affinity Switch for the Human Cannabinoid Receptor 2

Characterization of signal bias at the GLP-1 receptor induced by backbone modification of GLP-1

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