Remote control of glucose homeostasis in vivo using photopharmacology

Mehta, Zenobia B.; Johnston, Natalie R.; Nguyen-Tu, Marie Sophie; Broichhagen, Johannes; Schultz, Peter G.; Larner, Dean P.; Leclerc, Isabelle; Trauner, Dirk; Rutter, Guy A.; Hodson, David J.

doi:10.1038/s41598-017-00397-0

Cited by 40 publications

(35 citation statements)

References 41 publications

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“…2016 b ). However, there are disadvantages with photopharmacology: the lack of binary switch can complicate the optical control of cell function, UV illumination is generally required for the isomerisation step and toxicity and metabolite production need to be carefully assessed, just as for any drug, although the azobenzene itself appears to be well tolerated ( Mehta et al . 2017 ).…”

Section: New Tools For Understanding Beta Cell Heterogeneitymentioning

confidence: 99%

The role of beta cell heterogeneity in islet function and insulin release

Nasteska

Hodson

2018

Journal of Molecular Endocrinology

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It is becoming increasingly apparent that not all insulin-secreting beta cells are equal. Subtle differences exist at the transcriptomic and protein expression levels, with repercussions for beta cell survival/proliferation, calcium signalling and insulin release. Notably, beta cell heterogeneity displays plasticity during development, metabolic stress and type 2 diabetes mellitus (T2DM). Thus, heterogeneity or lack thereof may be an important contributor to beta cell failure during T2DM in both rodents and humans. The present review will discuss the molecular and cellular features of beta cell heterogeneity at both the single-cell and islet level, explore how this influences islet function and insulin release and look into the alterations that may occur during obesity and T2DM.

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Section: New Tools For Understanding Beta Cell Heterogeneitymentioning

confidence: 99%

The role of beta cell heterogeneity in islet function and insulin release

Nasteska

Hodson

2018

Journal of Molecular Endocrinology

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“…It should be noted that the stability of azobenzene compounds introduced ex vivo or in vivo has to be evaluated on a case-to-case basis as degradation of the diazene unit might occur depending on cell environment or azoreductase expression. While we have shown that this is not the case for polar compounds such as JB253 68 and JB558 69 , careful evaluation has to be performed before any clinical applications can be envisioned.…”

Section: Discussionmentioning

confidence: 98%

Optical control of a receptor-linked guanylyl cyclase using a photoswitchable peptidic hormone

et al. 2017

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The optical control over biological function with small photoswitchable molecules has gathered significant attention in the last decade. Herein, we describe the design and synthesis of a small library of photoswitchable peptidomimetics based upon human atrial natriuretic peptide (ANP), in which the photochromic amino acid [3-(3-aminomethyl)phenylazo]phenylacetic acid (AMPP) is incorporated into the peptide backbone. The endogeneous hormone ANP signals via the natriuretic peptide receptor A (NPR-A) through raising intracellular cGMP concentrations, and is involved in blood pressure regulation and sodium homeostasis, as well as lipid metabolism and pancreatic function. The cis-and trans-isomers of one of our peptidomimetics, termed TOP271, exhibit a four-fold difference in NPR-A mediated cGMP synthesis in vitro. Despite this seemingly small difference, TOP271 enables large, optically-induced conformational changes ex vivo and transforms the NPR-A into an endogenous photoswitch. Thus, application of TOP271 allows the reversible generation of cGMP using light and remote control can be afforded over vasoactivity in explanted murine aortic rings, as well as pancreatic beta cell function in islets of Langerhans. This study demonstrates the broad applicability of TOP271 to enzyme-dependent signalling processes, extends the toolbox of photoswitchable molecules to all classes of transmembrane receptors and utilizes photopharmacology to deduce receptor activation on a molecular level.

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“…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, the class B glucagon‐like peptide‐1 receptor, the adenosine, the dopamine and μ‐opioid receptor, and the muscarinic acetylcholine receptor . At the same time of the preparation of this manuscript, Westphal et al.…”

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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Remote control of glucose homeostasis in vivo using photopharmacology

Cited by 40 publications

References 41 publications

The role of beta cell heterogeneity in islet function and insulin release

The role of beta cell heterogeneity in islet function and insulin release

Optical control of a receptor-linked guanylyl cyclase using a photoswitchable peptidic hormone

The First Photochromic Affinity Switch for the Human Cannabinoid Receptor 2

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