Photohormones Enable Optical Control of the Peroxisome Proliferator-Activated Receptor γ (PPARγ)

Hinnah, Konstantin; Willems, Sabine; Heering, Jan; Hartrampf, Felix; Broichhagen, Johannes; Leippe, Philipp; Merk, Daniel; Trauner, Dirk

doi:10.1021/acs.jmedchem.0c00654

Cited by 30 publications

(18 citation statements)

References 51 publications

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“…These lipid analogues exhibit a hydrophobic azobenzene photoswitch in their lipid tail, allowing for retention of the headgroup and biological function of lipids while often enabling optical control of that function through differences in the bioactivities of the trans and cis forms . Photoswitchable lipids have yielded optical control of several biological targets, including ion channels, − G-protein-coupled receptors (GPCRs), − enzymes, , nuclear hormone receptors, − immune receptors, , as well as membrane properties. − Among the photolipids developed to date several are analogues of lipids implicated in PA metabolism, which include fatty acids ( FAAzo4 ), diacylglycerol ( PhoDAG and OptoDArG ), , lysophosphatidic acid ( AzoLPA ), and phosphatidylcholine ( AzoPC ) (Figure A,B).…”

Section: Introductionmentioning

confidence: 99%

Optical Control of Phosphatidic Acid Signaling

et al. 2021

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Phosphatidic acids (PAs) are glycerophospholipids that regulate key cell signaling pathways governing cell growth and proliferation, including the mTOR and Hippo pathways. Their acyl chains vary in tail length and degree of saturation, leading to marked differences in the signaling functions of different PA species. For example, in mTOR signaling, saturated forms of PA are inhibitory, whereas unsaturated forms are activating. To enable rapid control over PA signaling, we describe here the development of photoswitchable analogues of PA, termed AzoPA and dAzoPA , that contain azobenzene groups in one or both lipid tails, respectively. These photolipids enable optical control of their tail structure and can be reversibly switched between a straight trans form and a relatively bent cis form. We found that cis - dAzoPA selectively activates mTOR signaling, mimicking the bioactivity of unsaturated forms of PA. Further, in the context of Hippo signaling, whose growth-suppressing activity is blocked by PA, we found that the cis forms of both AzoPA and dAzoPA selectively inhibit this pathway. Collectively, these photoswitchable PA analogues enable optical control of mTOR and Hippo signaling, and we envision future applications of these probes to dissect the pleiotropic effects of physiological and pathological PA signaling.

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Section: Introductionmentioning

confidence: 99%

Optical Control of Phosphatidic Acid Signaling

et al. 2021

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“…6E), which reversibly formed a covalent bond with the cysteine thiol group. 67,68) Recently, Hinnah et al developed photoswitchable PPARγ ligands in which the aminoethoxy linker of rosiglitazone or GW1929 was substituted with an azo group 69) (Fig. 6E).…”

Section: Approaches For Pparγ Ligand Designmentioning

confidence: 99%

Insights into Dynamic Mechanism of Ligand Binding to Peroxisome Proliferator-Activated Receptor γ toward Potential Pharmacological Applications

Miyamae

2021

Biological & Pharmaceutical Bulletin

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Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor superfamily, which regulates the transcription of a variety of genes involved in lipid and glucose metabolism, inflammation, and cell proliferation. These functions correlate with the onset of type-2 diabetes, obesity, and immune disorders, which makes PPARγ a promising target for drug development. The majority of PPARγ functions are regulated by binding of small molecule ligands, which cause conformational changes of PPARγ followed by coregulator recruitment. The ligand-binding domain (LBD) of PPARγ contains a large Y-shaped cavity that can be occupied by various classes of compounds such as full agonists, partial agonists, natural lipids, and in some cases, a combination of multiple molecules. Several crystal structure studies have revealed the binding modes of these compounds in the LBD and insight into the resulting conformational changes. Notably, the apo form of the PPARγ LBD contains a highly mobile region that can be stabilized by ligand binding. Furthermore, recent biophysical investigations have shed light on the dynamic mechanism of how ligands induce conformational changes in PPARγ and result in functional output. This information may be useful for the design of new and repurposed structures of ligands that serve a different function from original compounds and more potent pharmacological effects with less undesirable clinical outcomes. This review provides an overview of the peculiar characteristics of the PPARγ LBD by examining a series of structural studies focused on the dynamic mechanism of binding and the potential applications of strategies for ligand screening and chemical labeling.

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“… 27 Such an approach has been gaining momentum also in photopharmacology in recent years, resulting in different applications for modeling: computer-assisted design 18 , 22 , 28 and a posteriori rationalization of the observed results. 29 − 32 However, proper structure-based design 33 , 34 (analysis of substitutions, reiterated cycles of design-test) is still an underexplored pathway in small-molecule-based approaches to regulating biological activity with light.…”

Section: Introductionmentioning

confidence: 99%

Hypothesis-Driven, Structure-Based Design in Photopharmacology: The Case of eDHFR Inhibitors

et al. 2022

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Photopharmacology uses light to regulate the biological activity of drugs. This precise control is obtained through the incorporation of molecular photoswitches into bioactive molecules. A major challenge for photopharmacology is the rational design of photoswitchable drugs that show light-induced activation. Computer-aided drug design is an attractive approach toward more effective, targeted design. Herein, we critically evaluated different structure-based approaches for photopharmacology with Escherichia coli dihydrofolate reductase (eDHFR) as a case study. Through the iterative examination of our hypotheses, we progressively tuned the design of azobenzene-based, photoswitchable eDHFR inhibitors in five design–make–switch–test–analyze cycles. Targeting a hydrophobic subpocket of the enzyme and a specific salt bridge only with the thermally metastable cis -isomer emerged as the most promising design strategy. We identified three inhibitors that could be activated upon irradiation and reached potencies in the low-nanomolar range. Above all, this systematic study provided valuable insights for future endeavors toward rational photopharmacology.

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Photohormones Enable Optical Control of the Peroxisome Proliferator-Activated Receptor γ (PPARγ)

Cited by 30 publications

References 51 publications

Optical Control of Phosphatidic Acid Signaling

Optical Control of Phosphatidic Acid Signaling

Insights into Dynamic Mechanism of Ligand Binding to Peroxisome Proliferator-Activated Receptor γ toward Potential Pharmacological Applications

Hypothesis-Driven, Structure-Based Design in Photopharmacology: The Case of eDHFR Inhibitors

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