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1
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Wei Y, Zi X, Zhai J, Zhang M, Li J, Sun Z, Ju M, Zhang X, Shen B. Exploring Endoplasmic Reticulum Dysfunction on Protein Phase Separation Using Viscosity-Sensitive Fluorescent Lifetime Probe. Anal Chem 2025; 97:10038-10045. [PMID: 40296325 DOI: 10.1021/acs.analchem.5c01131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/30/2025]
Abstract
Degenerative diseases are closely associated with protein phase transitions. Endoplasmic reticulum (ER), the primary site of protein synthesis, experiences homeostasis imbalance as the key trigger of the protein phase transition. Effective tools to monitor ER microenvironment changes are crucial for investigating protein phase behavior. In this work, we developed a set of viscosity-sensitive probes based on dicyanomethylene-4H-pyran (namely, VisDCM probes) with dual response of fluorescence intensity and fluorescence lifetime to local viscosity changes. Computational analysis demonstrated that fluorescence activation of VisDCM probes is due to the restricted accessible conical intersection mechanism under specific viscosity. Dual-color probes targeting the ER and protein of interest were designed. They revealed how ER stress regulates TDP-43 protein phase separation via Ca2+ signaling. In vitro experiments exhibited that TDP-43 phase separation is Ca2+-dependent. Increased Ca2+ promotes TDP-43 liquid-liquid phase separation and aggregation. Finally, fluorescence lifetime imaging was applied to map ERS-induced microenvironment changes. In summary, this work provides a novel toolbox to visualize protein phase transitions as well as highlights Ca2+ role in TDP-43 phase separation and aggregation, offering insights and potential therapies for degenerative diseases.
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Affiliation(s)
- Yu Wei
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, 1 Wenyuan Road, Nanjing 210023, China
| | - Xiangyu Zi
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, 1 Wenyuan Road, Nanjing 210023, China
| | - Jia Zhai
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, 1 Wenyuan Road, Nanjing 210023, China
| | - Man Zhang
- School of Psychology, Nanjing Normal University, 122 Ninghai Road, Gulou District, Nanjing, Jiangsu 210097, China
| | - Jiaqi Li
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, 1 Wenyuan Road, Nanjing 210023, China
- Room 1201, Building A, High tech Innovation Center, Guangqiao Road, Guangming District, Shenzhen 518132, China
| | - Zhenglong Sun
- Room 1201, Building A, High tech Innovation Center, Guangqiao Road, Guangming District, Shenzhen 518132, China
| | - Minzi Ju
- School of Psychology, Nanjing Normal University, 122 Ninghai Road, Gulou District, Nanjing, Jiangsu 210097, China
| | - Xin Zhang
- Department of Chemistry, Research Center for Industries of the Future, Westlake University, 600 Dunyu Road, Zhejiang, Hangzhou 310030, China
| | - Baoxing Shen
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, 1 Wenyuan Road, Nanjing 210023, China
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2
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Kiss E, Mester D, Bojtár M, Miskolczy Z, Biczók L, Hessz D, Kállay M, Kubinyi M. Supramolecular Control of the Photoisomerization of a Coumarin-Based Photoswitch. ACS OMEGA 2024; 9:51652-51664. [PMID: 39758680 PMCID: PMC11696389 DOI: 10.1021/acsomega.4c08106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 11/26/2024] [Accepted: 12/02/2024] [Indexed: 01/07/2025]
Abstract
The complex formation of the cationic stilbene-type photoswitch CP with the anionic macrocycles carboxylato-pillar[5]arene (WP5) and carboxylato-pillar[6]arene (WP6) has been investigated in aqueous solution by optical spectroscopic, NMR and isothermal calorimetric experiments and theoretical calculations. Subsequently, the photoisomerization reactions of the supramolecular complexes formed have been studied. CP consists of a 7-diethylamino-coumarin fluorophore and an N-methylpyridinium unit, which are connected via an ethene bridge. The trans isomer of CP is fluorescent, and its cis isomer is dark. The binding constants of the WP6 complexes of the two photoisomers of CP are larger by 2 orders of magnitude than those of the respective complexes with WP5, and trans-CP forms more stable complexes with the individual pillararenes than the cis isomer. As shown by NMR spectroscopic measurements and theoretical calculations, the two isomers of CP form external complexes with WP5 and inclusion complexes with WP6. On complexation with WP6, the quantum yields of both the trans-to-cis and cis-to-trans photoisomerization reactions of CP increase significantly, and the fluorescence quantum yield of trans-CP is also enhanced. These changes are due to the suppression of the TICT deactivation process, which is characteristic of 7-dialkylamino-coumarin derivatives.
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Affiliation(s)
- Etelka Kiss
- Department
of Physical Chemistry and Materials Science, Faculty of Chemical Technology
and Biotechnology, Budapest University of
Technology and Economics, Műegyetem rkp. 3, 1111 Budapest, Hungary
| | - Dávid Mester
- Department
of Physical Chemistry and Materials Science, Faculty of Chemical Technology
and Biotechnology, Budapest University of
Technology and Economics, Műegyetem rkp. 3, 1111 Budapest, Hungary
- MTA-BME
Lendület Quantum Chemistry Research Group, Budapest University of Technology and Economics, Műegyetem rkp. 3, 1111 Budapest, Hungary
- ELKH-BME
Quantum Chemistry Research Group, Budapest
University of Technology and Economics, Műegyetem rkp. 3, 1111 Budapest, Hungary
| | - Márton Bojtár
- Chemical
Biology Research Group, Institute of Organic Chemistry, HUN-REN Research Centre for Natural Sciences, Magyar tudósok krt. 2, 1117 Budapest, Hungary
| | - Zsombor Miskolczy
- Institute
of Materials and Environmental Chemistry, Research Centre for Natural
Sciences, HUN-REN Research Network, H-1519 Budapest, P.O. Box 286, Hungary
| | - László Biczók
- Institute
of Materials and Environmental Chemistry, Research Centre for Natural
Sciences, HUN-REN Research Network, H-1519 Budapest, P.O. Box 286, Hungary
| | - Dóra Hessz
- Department
of Physical Chemistry and Materials Science, Faculty of Chemical Technology
and Biotechnology, Budapest University of
Technology and Economics, Műegyetem rkp. 3, 1111 Budapest, Hungary
| | - Mihály Kállay
- Department
of Physical Chemistry and Materials Science, Faculty of Chemical Technology
and Biotechnology, Budapest University of
Technology and Economics, Műegyetem rkp. 3, 1111 Budapest, Hungary
- MTA-BME
Lendület Quantum Chemistry Research Group, Budapest University of Technology and Economics, Műegyetem rkp. 3, 1111 Budapest, Hungary
- ELKH-BME
Quantum Chemistry Research Group, Budapest
University of Technology and Economics, Műegyetem rkp. 3, 1111 Budapest, Hungary
| | - Miklós Kubinyi
- Department
of Physical Chemistry and Materials Science, Faculty of Chemical Technology
and Biotechnology, Budapest University of
Technology and Economics, Műegyetem rkp. 3, 1111 Budapest, Hungary
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3
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Wu X, Zhang Y, Song S, Liu S, Ma F, Ma R, Shi L. Functional nanochaperones for PEGylated insulin delivery in long-term glycemic control. Biomater Sci 2024; 12:5742-5752. [PMID: 39382287 DOI: 10.1039/d4bm01163e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/10/2024]
Abstract
PEGylation is a promising strategy for modulating the physicochemical properties and improving the therapeutic efficacy of protein drugs. However, the application of multi-PEGylation frequently results in diminished protein activity. A single low molecular weight PEG (5 kDa) modified at the amino terminus of the B chain preserves the biological activity of insulin and moderately improves its pharmacokinetics. Nonetheless, this modification offers limited protein stabilization. Furthermore, overdoses still carry the risk of hypoglycemia, posing challenges for the clinical application of PEGylated insulin. Here, we constructed multifunctional nanochaperones featuring phenylboronic acid (PBA) modified hydrophobic microdomains and nitrilotriacetic acid (NTA)-based coordination domains (PN-nChaps) for PEGylated insulin delivery. This delivery strategy effectively overcomes the limitations associated with PEGylation by enhancing the stability and reducing the immunogenicity of PEGylated insulin, while enabling glucose-responsive controlled release. PEGylated insulin with nanochaperone carrier demonstrates a prolonged half-life (t1/2 = 18.66 h), facilitates on-demand release, and minimizes the risk of hypoglycemia. This approach provides a safe and effective strategy for long-term glycemic management in diabetic patients.
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Affiliation(s)
- Xiaohui Wu
- Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, PR China.
- Haihe Laboratory of Sustainable Chemical Transformations, Tianjin 300192, PR China.
| | - Yanli Zhang
- Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, PR China.
- Haihe Laboratory of Sustainable Chemical Transformations, Tianjin 300192, PR China.
| | - Shuoshuo Song
- Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, PR China.
- Haihe Laboratory of Sustainable Chemical Transformations, Tianjin 300192, PR China.
| | - Sainan Liu
- Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, PR China.
- Haihe Laboratory of Sustainable Chemical Transformations, Tianjin 300192, PR China.
| | - Feihe Ma
- Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, PR China.
| | - Rujiang Ma
- Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, PR China.
| | - Linqi Shi
- Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, PR China.
- Haihe Laboratory of Sustainable Chemical Transformations, Tianjin 300192, PR China.
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Rath S, Patel S, Choppella S, Menon P, Garain T, Banerjee S, Ravva MK, Sen S. Photolytic ortho-Selective Amino Pyridylation of Aryl Isocyanates with N-Amino Pyridinium Ylides for the Synthesis of N-Arylsulfonyl Ureas. J Org Chem 2024; 89:14770-14784. [PMID: 39373291 DOI: 10.1021/acs.joc.4c01408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/08/2024]
Abstract
Herein, we report an expedient synthesis of aryl sulfonyl ureas 4 and 5 from N-amino pyridinium ylides and aryl isocyanates. N-Aminopyridinium ylides 3 are synthesized via blue light-emitting diode irradiation of pyridine/isoquinoline and appropriate iminoiodinanes. The strategy involved a hitherto unknown carboamination of imine moieties (of aryl isocyanates) via a three-component reaction of pyridine derivatives/isoquinoline 1, N-aryl sulfonyl iminoiodinanes 2, and numerous aryl isocyanates at room temperature in 2-methyl tetrahydrofuran to afford the target compounds in moderate to excellent yields. N-Arylpyridinium ylides 3 (as intermediates) undergo a [3+2] cycloaddition with the aryl isocyanates followed by the aromatization of the pyridine/isoquinoline moiety to afford compounds 4. On the basis of the substitution pattern among the reactants, in some cases pyridine extrusion occurs during the reaction to afford depyridinylated aryl sulfonyl ureas 5. In general, isocyanates are used as dipolarophiles in [3+2] cycloaddition reactions. However, regioselective amino pyridylation of these species is a first. Control experiments and density functional theory calculations elucidate the reaction mechanism. The batch process of the protocol could be seamlessly transferred to the photoflow synthesis.
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Affiliation(s)
- Suchismita Rath
- Department of Chemistry, School of Natural Sciences, Shiv Nadar Institution of Eminence Deemed to be University, Dadri, Chithera, Gautam Buddha Nagar, UP 201314, India
| | - Shreemad Patel
- Department of Chemistry, School of Natural Sciences, Shiv Nadar Institution of Eminence Deemed to be University, Dadri, Chithera, Gautam Buddha Nagar, UP 201314, India
| | | | - Pranoy Menon
- Department of Chemistry, School of Natural Sciences, Shiv Nadar Institution of Eminence Deemed to be University, Dadri, Chithera, Gautam Buddha Nagar, UP 201314, India
| | - Tanya Garain
- Molecular Biosciences, Middle Tennessee State University, Murfreesboro, Tennessee 37132-0001, United States
| | - Souvik Banerjee
- Molecular Biosciences, Middle Tennessee State University, Murfreesboro, Tennessee 37132-0001, United States
- Department of Chemistry, Middle Tennessee State University, Murfreesboro, Tennessee 37132, United States
| | | | - Subhabrata Sen
- Department of Chemistry, School of Natural Sciences, Shiv Nadar Institution of Eminence Deemed to be University, Dadri, Chithera, Gautam Buddha Nagar, UP 201314, India
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5
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Deng X, Peng D, Yao Y, Huang K, Wang J, Ma Z, Fu J, Xu Y. Optogenetic therapeutic strategies for diabetes mellitus. J Diabetes 2024; 16:e13557. [PMID: 38751366 PMCID: PMC11096815 DOI: 10.1111/1753-0407.13557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 02/28/2024] [Accepted: 03/11/2024] [Indexed: 05/18/2024] Open
Abstract
Diabetes mellitus (DM) is a common chronic disease affecting humans globally. It is characterized by abnormally elevated blood glucose levels due to the failure of insulin production or reduction of insulin sensitivity and functionality. Insulin and glucagon-like peptide (GLP)-1 replenishment or improvement of insulin resistance are the two major strategies to treat diabetes. Recently, optogenetics that uses genetically encoded light-sensitive proteins to precisely control cell functions has been regarded as a novel therapeutic strategy for diabetes. Here, we summarize the latest development of optogenetics and its integration with synthetic biology approaches to produce light-responsive cells for insulin/GLP-1 production, amelioration of insulin resistance and neuromodulation of insulin secretion. In addition, we introduce the development of cell encapsulation and delivery methods and smart bioelectronic devices for the in vivo application of optogenetics-based cell therapy in diabetes. The remaining challenges for optogenetics-based cell therapy in the clinical translational study are also discussed.
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Affiliation(s)
- Xin Deng
- Department of EndocrinologyChildren's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child HealthHangzhouChina
- Department of Biomedical Engineering, MOE Key Laboratory of Biomedical Engineering, Zhejiang Provincial Key Laboratory of Cardio‐Cerebral Vascular Detection Technology and Medicinal Effectiveness Appraisal, Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine for Clinical Evaluation and Translational ResearchZhejiang UniversityHangzhouChina
| | - Dandan Peng
- Department of EndocrinologyChildren's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child HealthHangzhouChina
| | - Yuanfa Yao
- Department of Biomedical Engineering, MOE Key Laboratory of Biomedical Engineering, Zhejiang Provincial Key Laboratory of Cardio‐Cerebral Vascular Detection Technology and Medicinal Effectiveness Appraisal, Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine for Clinical Evaluation and Translational ResearchZhejiang UniversityHangzhouChina
| | - Ke Huang
- Department of EndocrinologyChildren's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child HealthHangzhouChina
| | - Jinling Wang
- Department of EndocrinologyChildren's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child HealthHangzhouChina
| | - Zhihao Ma
- Department of Biomedical Engineering, MOE Key Laboratory of Biomedical Engineering, Zhejiang Provincial Key Laboratory of Cardio‐Cerebral Vascular Detection Technology and Medicinal Effectiveness Appraisal, Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine for Clinical Evaluation and Translational ResearchZhejiang UniversityHangzhouChina
| | - Junfen Fu
- Department of EndocrinologyChildren's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child HealthHangzhouChina
| | - Yingke Xu
- Department of EndocrinologyChildren's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child HealthHangzhouChina
- Department of Biomedical Engineering, MOE Key Laboratory of Biomedical Engineering, Zhejiang Provincial Key Laboratory of Cardio‐Cerebral Vascular Detection Technology and Medicinal Effectiveness Appraisal, Zhejiang Provincial Key Laboratory of Traditional Chinese Medicine for Clinical Evaluation and Translational ResearchZhejiang UniversityHangzhouChina
- Binjiang Institute of Zhejiang UniversityHangzhouChina
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6
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Pfeffer ME, DiFrancesco ML, Marchesi A, Galluzzi F, Moschetta M, Rossini A, Francia S, Franz CM, Fok Y, Valotteau C, Paternò GM, Redondo Morata L, Vacca F, Mattiello S, Magni A, Maragliano L, Beverina L, Mattioli G, Lanzani G, Baldelli P, Colombo E, Benfenati F. Nanoactuator for Neuronal Optoporation. ACS NANO 2024; 18:12427-12452. [PMID: 38687909 DOI: 10.1021/acsnano.4c01672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/02/2024]
Abstract
Light-driven modulation of neuronal activity at high spatial-temporal resolution is becoming of high interest in neuroscience. In addition to optogenetics, nongenetic membrane-targeted nanomachines that alter the electrical state of the neuronal membranes are in demand. Here, we engineered and characterized a photoswitchable conjugated compound (BV-1) that spontaneously partitions into the neuronal membrane and undergoes a charge transfer upon light stimulation. The activity of primary neurons is not affected in the dark, whereas millisecond light pulses of cyan light induce a progressive decrease in membrane resistance and an increase in inward current matched to a progressive depolarization and action potential firing. We found that illumination of BV-1 induces oxidation of membrane phospholipids, which is necessary for the electrophysiological effects and is associated with decreased membrane tension and increased membrane fluidity. Time-resolved atomic force microscopy and molecular dynamics simulations performed on planar lipid bilayers revealed that the underlying mechanism is a light-driven formation of pore-like structures across the plasma membrane. Such a phenomenon decreases membrane resistance and increases permeability to monovalent cations, namely, Na+, mimicking the effects of antifungal polyenes. The same effect on membrane resistance was also observed in nonexcitable cells. When sustained light stimulations are applied, neuronal swelling and death occur. The light-controlled pore-forming properties of BV-1 allow performing "on-demand" light-induced membrane poration to rapidly shift from cell-attached to perforated whole-cell patch-clamp configuration. Administration of BV-1 to ex vivo retinal explants or in vivo primary visual cortex elicited neuronal firing in response to short trains of light stimuli, followed by activity silencing upon prolonged light stimulations. BV-1 represents a versatile molecular nanomachine whose properties can be exploited to induce either photostimulation or space-specific cell death, depending on the pattern and duration of light stimulation.
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Affiliation(s)
- Marlene E Pfeffer
- Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132 Genova, Italy
- Department of Experimental Medicine, University of Genova, Viale Benedetto XV 3, 16132 Genova, Italy
| | | | - Arin Marchesi
- WPI Nano Life Science Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
- Department of Experimental and Clinical Medicine, Università Politecnica delle Marche, Via Tronto 10/a, 60126 Torrette di Ancona, Italy
| | - Filippo Galluzzi
- Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132 Genova, Italy
- The Open University Affiliated Research Centre at Istituto Italiano di Tecnologia (ARC@IIT), Via Morego 30, 16163 Genova, Italy
| | - Matteo Moschetta
- Center for Nano Science and Technology, Istituto Italiano di Tecnologia, Via Raffaele Rubattino 81, 20134 Milano, Italy
| | - Andrea Rossini
- Center for Nano Science and Technology, Istituto Italiano di Tecnologia, Via Raffaele Rubattino 81, 20134 Milano, Italy
| | - Simona Francia
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova, Italy
| | - Clemens M Franz
- WPI Nano Life Science Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
| | - Yulia Fok
- Aix-Marseille University, INSERM, DyNaMo, Turing Centre for Living Systems, 163 Avenue de Luminy, 13288 Marseille Cedex 09, France
| | - Claire Valotteau
- Aix-Marseille University, INSERM, DyNaMo, Turing Centre for Living Systems, 163 Avenue de Luminy, 13288 Marseille Cedex 09, France
| | - Giuseppe Maria Paternò
- Center for Nano Science and Technology, Istituto Italiano di Tecnologia, Via Raffaele Rubattino 81, 20134 Milano, Italy
- Department of Physics, Politecnico di Milano, Piazza Leonardo Da Vinci, 32, 20133 Milan, Italy
| | - Lorena Redondo Morata
- Aix-Marseille University, INSERM, DyNaMo, Turing Centre for Living Systems, 163 Avenue de Luminy, 13288 Marseille Cedex 09, France
| | - Francesca Vacca
- Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132 Genova, Italy
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova, Italy
| | - Sara Mattiello
- Department of Material Science, Bicocca University, Via Roberto Cozzi 55, 20126 Milano, Italy
| | - Arianna Magni
- Center for Nano Science and Technology, Istituto Italiano di Tecnologia, Via Raffaele Rubattino 81, 20134 Milano, Italy
- Department of Physics, Politecnico di Milano, Piazza Leonardo Da Vinci, 32, 20133 Milan, Italy
| | - Luca Maragliano
- Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132 Genova, Italy
- Department of Life and Environmental Sciences, Università Politecnica delle Marche, Via Brecce Bianche, 60131 Ancona, Italy
| | - Luca Beverina
- Department of Material Science, Bicocca University, Via Roberto Cozzi 55, 20126 Milano, Italy
| | - Giuseppe Mattioli
- Istituto di Struttura della Materia, Consiglio Nazionale delle Ricerche (CNR-ISM), Via Salaria km 29.300, 00015 Monterotondo (RM), Italy
| | - Guglielmo Lanzani
- Center for Nano Science and Technology, Istituto Italiano di Tecnologia, Via Raffaele Rubattino 81, 20134 Milano, Italy
- Department of Physics, Politecnico di Milano, Piazza Leonardo Da Vinci, 32, 20133 Milan, Italy
| | - Pietro Baldelli
- Department of Experimental Medicine, University of Genova, Viale Benedetto XV 3, 16132 Genova, Italy
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova, Italy
| | - Elisabetta Colombo
- Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132 Genova, Italy
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova, Italy
| | - Fabio Benfenati
- Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Largo Rosanna Benzi 10, 16132 Genova, Italy
- IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova, Italy
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7
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Bacsa B, Hopl V, Derler I. Synthetic Biology Meets Ca 2+ Release-Activated Ca 2+ Channel-Dependent Immunomodulation. Cells 2024; 13:468. [PMID: 38534312 PMCID: PMC10968988 DOI: 10.3390/cells13060468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 02/27/2024] [Accepted: 03/05/2024] [Indexed: 03/28/2024] Open
Abstract
Many essential biological processes are triggered by the proximity of molecules. Meanwhile, diverse approaches in synthetic biology, such as new biological parts or engineered cells, have opened up avenues to precisely control the proximity of molecules and eventually downstream signaling processes. This also applies to a main Ca2+ entry pathway into the cell, the so-called Ca2+ release-activated Ca2+ (CRAC) channel. CRAC channels are among other channels are essential in the immune response and are activated by receptor-ligand binding at the cell membrane. The latter initiates a signaling cascade within the cell, which finally triggers the coupling of the two key molecular components of the CRAC channel, namely the stromal interaction molecule, STIM, in the ER membrane and the plasma membrane Ca2+ ion channel, Orai. Ca2+ entry, established via STIM/Orai coupling, is essential for various immune cell functions, including cytokine release, proliferation, and cytotoxicity. In this review, we summarize the tools of synthetic biology that have been used so far to achieve precise control over the CRAC channel pathway and thus over downstream signaling events related to the immune response.
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Affiliation(s)
- Bernadett Bacsa
- Division of Medical Physics und Biophysics, Medical University of Graz, A-8010 Graz, Austria;
| | - Valentina Hopl
- Institute of Biophysics, JKU Life Science Center, Johannes Kepler University Linz, A-4020 Linz, Austria;
| | - Isabella Derler
- Institute of Biophysics, JKU Life Science Center, Johannes Kepler University Linz, A-4020 Linz, Austria;
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8
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Rückert A, Ast J, Hasib A, Nasteska D, Viloria K, Broichhagen J, Hodson DJ. Fine-tuned photochromic sulfonylureas for optical control of beta cell Ca 2+ fluxes. Diabet Med 2023; 40:e15220. [PMID: 37669696 PMCID: PMC10947021 DOI: 10.1111/dme.15220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/30/2023] [Accepted: 09/01/2023] [Indexed: 09/07/2023]
Abstract
We previously developed, synthesized and tested light-activated sulfonylureas for optical control of KATP channels and pancreatic beta cell activity in vitro and in vivo. Such technology relies on installation of azobenzene photoswitches onto the sulfonylurea backbone, affording light-dependent isomerization, alteration in ligand affinity for SUR1 and hence KATP channel conductance. Inspired by molecular dynamics simulations and to further improve photoswitching characteristics, we set out to develop a novel push-pull closed ring azobenzene unit, before installing this on the sulfonylurea glimepiride as a small molecule recipient. Three fine-tuned, light-activated sulfonylureas were synthesized, encompassing azetidine, pyrrolidine and piperidine closed rings. Azetidine-, pyrrolidine- and piperidine-based sulfonylureas all increased beta cell Ca2+ -spiking activity upon continuous blue light illumination, similarly to first generation JB253. Notably, the pyrrolidine-based sulfonylurea showed superior switch OFF performance to JB253. As such, third generation sulfonylureas afford more precise optical control over primary pancreatic beta cells, and showcase the potential of pyrrolidine-azobenzenes as chemical photoswitches across drug classes.
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Affiliation(s)
| | - Julia Ast
- Institute of Metabolism and Systems Research (IMSR), and Centre of Membrane Proteins and Receptors (COMPARE)University of BirminghamBirminghamUK
| | - Annie Hasib
- Institute of Metabolism and Systems Research (IMSR), and Centre of Membrane Proteins and Receptors (COMPARE)University of BirminghamBirminghamUK
| | - Daniela Nasteska
- Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, Churchill Hospital, Radcliffe Department of MedicineUniversity of OxfordOxfordUK
| | - Katrina Viloria
- Institute of Metabolism and Systems Research (IMSR), and Centre of Membrane Proteins and Receptors (COMPARE)University of BirminghamBirminghamUK
- Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, Churchill Hospital, Radcliffe Department of MedicineUniversity of OxfordOxfordUK
| | | | - David J. Hodson
- Institute of Metabolism and Systems Research (IMSR), and Centre of Membrane Proteins and Receptors (COMPARE)University of BirminghamBirminghamUK
- Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, Churchill Hospital, Radcliffe Department of MedicineUniversity of OxfordOxfordUK
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9
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Axelrod S, Shakhnovich E, Gómez-Bombarelli R. Mapping the Space of Photoswitchable Ligands and Photodruggable Proteins with Computational Modeling. J Chem Inf Model 2023; 63:5794-5802. [PMID: 37671878 DOI: 10.1021/acs.jcim.3c00484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/07/2023]
Abstract
Light-activated drugs are a promising way to localize biological activity and minimize side effects. However, their development is complicated by the numerous photophysical and biological properties that must be simultaneously optimized. To accelerate the design of photoactive drugs, we describe a procedure that combines ligand-protein docking with chemical property prediction based on machine learning (ML). We apply this procedure to 58 proteins and 9000 photo-drug candidates based on azobenzene cis-trans isomerism. We find that most proteins display a preference for trans isomers over cis and that the binding affinities of nominally active/inactive pairs are in fact highly correlated. These findings have significant value for photopharmacology research, and reinforce the need for virtual screening to identify compounds with rare desirable properties. Further, we combine our procedure with quantum chemical validation to identify promising candidates for the photoactive inhibition of PARP1, an enzyme that is over-expressed in cancer cells. The top compounds are predicted to have long-lived active forms, differential bioactivity, and absorption in the near-infrared therapeutic window.
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Affiliation(s)
- Simon Axelrod
- Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States
- Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
| | - Eugene Shakhnovich
- Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States
| | - Rafael Gómez-Bombarelli
- Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
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10
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Sridhar V, Yildiz E, Rodríguez‐Camargo A, Lyu X, Yao L, Wrede P, Aghakhani A, Akolpoglu BM, Podjaski F, Lotsch BV, Sitti M. Designing Covalent Organic Framework-Based Light-Driven Microswimmers toward Therapeutic Applications. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2023; 35:e2301126. [PMID: 37003701 PMCID: PMC11475396 DOI: 10.1002/adma.202301126] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 03/18/2023] [Indexed: 06/19/2023]
Abstract
While micromachines with tailored functionalities enable therapeutic applications in biological environments, their controlled motion and targeted drug delivery in biological media require sophisticated designs for practical applications. Covalent organic frameworks (COFs), a new generation of crystalline and nanoporous polymers, offer new perspectives for light-driven microswimmers in heterogeneous biological environments including intraocular fluids, thus setting the stage for biomedical applications such as retinal drug delivery. Two different types of COFs, uniformly spherical TABP-PDA-COF sub-micrometer particles and texturally nanoporous, micrometer-sized TpAzo-COF particles are described and compared as light-driven microrobots. They can be used as highly efficient visible-light-driven drug carriers in aqueous ionic and cellular media. Their absorption ranging down to red light enables phototaxis even in deeper and viscous biological media, while the organic nature of COFs ensures their biocompatibility. Their inherently porous structures with ≈2.6 and ≈3.4 nm pores, and large surface areas allow for targeted and efficient drug loading even for insoluble drugs, which can be released on demand. Additionally, indocyanine green (ICG) dye loading in the pores enables photoacoustic imaging, optical coherence tomography, and hyperthermia in operando conditions. This real-time visualization of the drug-loaded COF microswimmers enables unique insights into the action of photoactive porous drug carriers for therapeutic applications.
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Affiliation(s)
- Varun Sridhar
- Physical Intelligence DepartmentMax Planck Institute for Intelligent Systems70569StuttgartGermany
| | - Erdost Yildiz
- Physical Intelligence DepartmentMax Planck Institute for Intelligent Systems70569StuttgartGermany
| | - Andrés Rodríguez‐Camargo
- Nanochemistry DepartmentMax Planck Institute for Solid State Research70569StuttgartGermany
- Department of ChemistryUniversity of Stuttgart70569StuttgartGermany
| | - Xianglong Lyu
- Physical Intelligence DepartmentMax Planck Institute for Intelligent Systems70569StuttgartGermany
| | - Liang Yao
- Nanochemistry DepartmentMax Planck Institute for Solid State Research70569StuttgartGermany
| | - Paul Wrede
- Physical Intelligence DepartmentMax Planck Institute for Intelligent Systems70569StuttgartGermany
- Institute for Biomedical EngineeringETH Zurich8092ZurichSwitzerland
| | - Amirreza Aghakhani
- Physical Intelligence DepartmentMax Planck Institute for Intelligent Systems70569StuttgartGermany
| | - Birgul M. Akolpoglu
- Physical Intelligence DepartmentMax Planck Institute for Intelligent Systems70569StuttgartGermany
- Institute for Biomedical EngineeringETH Zurich8092ZurichSwitzerland
| | - Filip Podjaski
- Nanochemistry DepartmentMax Planck Institute for Solid State Research70569StuttgartGermany
- Department of ChemistryImperial College LondonW12 0BZLondonUK
| | - Bettina V. Lotsch
- Nanochemistry DepartmentMax Planck Institute for Solid State Research70569StuttgartGermany
- Department of ChemistryUniversity of Stuttgart70569StuttgartGermany
- Cluster of Excellence e‐conversion85748Lichtenbergstrasse 4GarchingGermany
- Department of ChemistryUniversity of Munich (LMU)81377MunichGermany
| | - Metin Sitti
- Physical Intelligence DepartmentMax Planck Institute for Intelligent Systems70569StuttgartGermany
- Institute for Biomedical EngineeringETH Zurich8092ZurichSwitzerland
- School of Medicine and College of EngineeringKoç University34450IstanbulTurkey
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11
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Mehrpour O, Saeedi F, Nakhaee S, Tavakkoli Khomeini F, Hadianfar A, Amirabadizadeh A, Hoyte C. Comparison of decision tree with common machine learning models for prediction of biguanide and sulfonylurea poisoning in the United States: an analysis of the National Poison Data System. BMC Med Inform Decis Mak 2023; 23:60. [PMID: 37024869 PMCID: PMC10080923 DOI: 10.1186/s12911-022-02095-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 12/26/2022] [Indexed: 04/08/2023] Open
Abstract
BACKGROUND Biguanides and sulfonylurea are two classes of anti-diabetic medications that have commonly been prescribed all around the world. Diagnosis of biguanide and sulfonylurea exposures is based on history taking and physical examination; thus, physicians might misdiagnose these two different clinical settings. We aimed to conduct a study to develop a model based on decision tree analysis to help physicians better diagnose these poisoning cases. METHODS The National Poison Data System was used for this six-year retrospective cohort study.The decision tree model, common machine learning models multi layers perceptron, stochastic gradient descent (SGD), Adaboosting classiefier, linear support vector machine and ensembling methods including bagging, voting and stacking methods were used. The confusion matrix, precision, recall, specificity, f1-score, and accuracy were reported to evaluate the model's performance. RESULTS Of 6183 participants, 3336 patients (54.0%) were identified as biguanides exposures, and the remaining were those with sulfonylureas exposures. The decision tree model showed that the most important clinical findings defining biguanide and sulfonylurea exposures were hypoglycemia, abdominal pain, acidosis, diaphoresis, tremor, vomiting, diarrhea, age, and reasons for exposure. The specificity, precision, recall, f1-score, and accuracy of all models were greater than 86%, 89%, 88%, and 88%, respectively. The lowest values belong to SGD model. The decision tree model has a sensitivity (recall) of 93.3%, specificity of 92.8%, precision of 93.4%, f1_score of 93.3%, and accuracy of 93.3%. CONCLUSION Our results indicated that machine learning methods including decision tree and ensembling methods provide a precise prediction model to diagnose biguanides and sulfonylureas exposure.
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Affiliation(s)
- Omid Mehrpour
- Data Science Institute, Southern Methodist University, Dallas, TX, USA.
- Medical Toxicology and Drug Abuse Research Center (MTDRC), Birjand University of Medical Sciences, Birjand, Iran.
| | - Farhad Saeedi
- Medical Toxicology and Drug Abuse Research Center (MTDRC), Birjand University of Medical Sciences, Birjand, Iran
- Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran
| | - Samaneh Nakhaee
- Medical Toxicology and Drug Abuse Research Center (MTDRC), Birjand University of Medical Sciences, Birjand, Iran
| | | | - Ali Hadianfar
- Department of Epidemiology and Biostatistics, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alireza Amirabadizadeh
- Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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12
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Cataldi E, Raschig M, Gutmann M, Geppert PT, Ruopp M, Schock M, Gerwe H, Bertermann R, Meinel L, Finze M, Nowak-Król A, Decker M, Lühmann T. Amber Light Control of Peptide Secondary Structure by a Perfluoroaromatic Azobenzene Photoswitch. Chembiochem 2023; 24:e202200570. [PMID: 36567253 DOI: 10.1002/cbic.202200570] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 12/23/2022] [Accepted: 12/23/2022] [Indexed: 12/27/2022]
Abstract
The incorporation of photoswitches into the molecular structure of peptides and proteins enables their dynamic photocontrol in complex biological systems. Here, a perfluorinated azobenzene derivative triggered by amber light was site-specifically conjugated to cysteines in a helical peptide by perfluoroarylation chemistry. In response to the photoisomerization (trans→cis) of the conjugated azobenzene with amber light, the secondary structure of the peptide was modulated from a disorganized into an amphiphilic helical structure.
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Affiliation(s)
- Eleonora Cataldi
- Universität Würzburg, Institute for Pharmacy and Food Chemistry, Am Hubland, 97074, Würzburg, Germany
| | - Martina Raschig
- Universität Würzburg, Institute for Pharmacy and Food Chemistry, Am Hubland, 97074, Würzburg, Germany
| | - Marcus Gutmann
- Universität Würzburg, Institute for Pharmacy and Food Chemistry, Am Hubland, 97074, Würzburg, Germany
| | - Patrick T Geppert
- Universität Würzburg, Institute of Inorganic Chemistry and Institute for Sustainable Chemistry and Catalysis with Boron, Am Hubland, 97074, Würzburg, Germany
| | - Matthias Ruopp
- Universität Würzburg, Institute for Pharmacy and Food Chemistry, Am Hubland, 97074, Würzburg, Germany
| | - Marvin Schock
- Universität Würzburg, Institute for Pharmacy and Food Chemistry, Am Hubland, 97074, Würzburg, Germany
| | - Hubert Gerwe
- Universität Würzburg, Institute for Pharmacy and Food Chemistry, Am Hubland, 97074, Würzburg, Germany
| | - Rüdiger Bertermann
- Universität Würzburg, Institute of Inorganic Chemistry and Institute for Sustainable Chemistry and Catalysis with Boron, Am Hubland, 97074, Würzburg, Germany
| | - Lorenz Meinel
- Universität Würzburg, Institute for Pharmacy and Food Chemistry, Am Hubland, 97074, Würzburg, Germany.,Helmholtz Institute for RNA-Based Infection Research (HIRI), Helmholtz Center for Infection Research (HZI), 97080, Würzburg, Germany
| | - Maik Finze
- Universität Würzburg, Institute of Inorganic Chemistry and Institute for Sustainable Chemistry and Catalysis with Boron, Am Hubland, 97074, Würzburg, Germany
| | - Agnieszka Nowak-Król
- Universität Würzburg, Institute of Inorganic Chemistry and Institute for Sustainable Chemistry and Catalysis with Boron, Am Hubland, 97074, Würzburg, Germany
| | - Michael Decker
- Universität Würzburg, Institute for Pharmacy and Food Chemistry, Am Hubland, 97074, Würzburg, Germany
| | - Tessa Lühmann
- Universität Würzburg, Institute for Pharmacy and Food Chemistry, Am Hubland, 97074, Würzburg, Germany
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13
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Ziani Z, Cobo S, Loiseau F, Jouvenot D, Lognon E, Boggio-Pasqua M, Royal G. All Visible Light Photoswitch Based on the Dimethyldihydropyrene Unit Operating in Aqueous Solutions with High Quantum Yields. JACS AU 2023; 3:131-142. [PMID: 36711101 PMCID: PMC9875246 DOI: 10.1021/jacsau.2c00552] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 11/15/2022] [Accepted: 11/15/2022] [Indexed: 06/18/2023]
Abstract
Molecular systems and devices whose properties can be modulated using light as an external stimulus are the subject of numerous research studies in the fields of materials and life sciences. In this context, the use of photochromic compounds that reversibly switch upon light irradiation is particularly attractive. However, for many envisioned applications, and in particular for biological purposes, illumination with harmful UV light must be avoided and these photoactivable systems must operate in aqueous media. In this context, we have designed a benzo[e]-fused dimethyldihydropyrene compound bearing a methyl-pyridinium electroacceptor group that meets these requirements. This compound (closed state) is able to reversibly isomerize under aerobic conditions into its corresponding cyclophanediene form (open isomer) through the opening of its central carbon-carbon bond. Both the photo-opening and the reverse photoclosing processes are triggered by visible light illumination and proceed with high quantum yields (respectively 14.5% yield at λ = 680 nm and quantitative quantum yield at λ = 470 nm, in water). This system has been investigated by nuclear magnetic resonance and absorption spectroscopy, and the efficient photoswitching behavior was rationalized by spin-flip time-dependent density functional theory calculations. In addition, it is demonstrated that the isomerization from the open to the closed form can be electrocatalytically triggered.
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Affiliation(s)
- Zakaria Ziani
- Univ.
Grenoble Alpes, CNRS, DCM, Grenoble38000, France
| | - Saioa Cobo
- Univ.
Grenoble Alpes, CNRS, DCM, Grenoble38000, France
| | | | | | - Elise Lognon
- LCPQ
UMR 5626, CNRS et Université Toulouse
III − Paul Sabatier, 118 route de Narbonne, Toulouse31062, France
| | - Martial Boggio-Pasqua
- LCPQ
UMR 5626, CNRS et Université Toulouse
III − Paul Sabatier, 118 route de Narbonne, Toulouse31062, France
| | - Guy Royal
- Univ.
Grenoble Alpes, CNRS, DCM, Grenoble38000, France
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14
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Emerging molecular technologies for light-mediated modulation of pancreatic beta-cell function. Mol Metab 2022; 64:101552. [PMID: 35863638 PMCID: PMC9352964 DOI: 10.1016/j.molmet.2022.101552] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 07/13/2022] [Accepted: 07/13/2022] [Indexed: 11/22/2022] Open
Abstract
Background Optogenetic modalities as well as optochemical and photopharmacological strategies, collectively termed optical methods, have revolutionized the control of cellular functions via light with great spatiotemporal precision. In comparison to the major advances in the photomodulation of signaling activities noted in neuroscience, similar applications to endocrine cells of the pancreas, particularly insulin-producing β-cells, have been limited. The availability of tools allowing light-mediated changes in the trafficking of ions such as K+ and Ca2+ and signaling intermediates such as cyclic adenosine monophosphate (cAMP), renders β-cells and their glucose-stimulated insulin secretion (GSIS) amenable to optoengineering for drug-free control of blood sugar. Scope of review The molecular circuit of the GSIS in β-cells is described with emphasis on intermediates which are targetable for optical intervention. Various pharmacological agents modifying the release of insulin are reviewed along with their documented side effects. These are contrasted with optical approaches, which have already been employed for engineering β-cell function or are considered for future such applications. Principal obstacles are also discussed as the implementation of optogenetics is pondered for tissue engineering and biology applications of the pancreas. Major Conclusions Notable advances in optogenetic, optochemical and photopharmacological tools are rendering feasible the smart engineering of pancreatic cells and tissues with light-regulated function paving the way for novel solutions for addressing pancreatic pathologies including diabetes.
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15
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Wang H, Li L. Comprehensive Evaluation of Probiotic Property, Hypoglycemic Ability and Antioxidant Activity of Lactic Acid Bacteria. Foods 2022; 11:foods11091363. [PMID: 35564086 PMCID: PMC9105430 DOI: 10.3390/foods11091363] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 05/02/2022] [Accepted: 05/05/2022] [Indexed: 02/01/2023] Open
Abstract
Taking lactic acid bacteria is an important strategy to alleviate or prevent diabetes, but the candidate strains with good genetic stability and excellent functions still need to be supplemented. In this study, the hypoglycemic ability (α-amylase, α-glucosidase and dipeptidyl peptidase 4), probiotic property and antioxidant activity of lactic acid bacteria were comprehensively evaluated by a principal component analysis (PCA) and analytic hierarchy process (AHP). The results showed that Lactobacillus paracasei(L. paracasei) had a higher survival rate (82.78%) in gastric juice and good tolerance to bile salt, and can be colonized in HT-29 cells. L. paracasei had a remarkable inhibitive activity of α-amylase (82.21%), α-glucosidase (84.29%) and dipeptidyl peptidase 4 (42.51%). L. paracasei had better scavenging activity of free radicals, total antioxidant activity (FRAP) and superoxide dismutase activity. According to the scores of the PCA, L. paracasei had the best hypoglycemic ability, and Lactococcus lactis (L. lactis) had the highest probiotic property. According to AHP, L. paracasei was the best potential hypoglycemic probiotic; furthermore, L. lactis showed the highest comprehensive performance except Lactobacillus. All lactic acid bacteria in this test had good safety. L. paracasei is expected to become a new potential hypoglycemic strain.
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Affiliation(s)
- Hongyu Wang
- State Key Laboratory of Dairy Biotechnology, Shanghai Engineering Research Center of Dairy Biotechnology, Dairy Research Institute, Bright Dairy & Food Co., Ltd., Shanghai 200436, China;
- College of Food Science, Northeast Agricultural University, Harbin 150030, China
| | - Liang Li
- State Key Laboratory of Dairy Biotechnology, Shanghai Engineering Research Center of Dairy Biotechnology, Dairy Research Institute, Bright Dairy & Food Co., Ltd., Shanghai 200436, China;
- College of Food Science, Northeast Agricultural University, Harbin 150030, China
- Correspondence: ; Tel.: +86-0451-55190477; Fax: +86-0451-55190577
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16
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Fu W, Shao Z, Sun X, Zhou C, Xu Z, Zhang Y, Cheng J, Li Z, Shao X. Reversible Regulation of Succinate Dehydrogenase by Tools of Photopharmacology. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:4279-4290. [PMID: 35357145 DOI: 10.1021/acs.jafc.1c08198] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Succinate dehydrogenase (SDH) is extremely important in metabolic function and biological processes. Modulation of SDH has been reported to be a promising therapeutic target to SDH mutations. Current measures for the regulation of SDH are scarce, and precise and reversible modulation of SDH still remains challenging. Herein, a powerful tool for reversible optical control of SDH was proposed and evaluated utilizing the technology of photopharmacology. We reported photochromic ligands (PCLs), azobenzene-pyrazole amides (APAs), that exert light-dependent inhibition effects on SDH. Physicochemical property tests and biological assays were conducted to demonstrate the feasibility of modulating SDH. In this paper, common agricultural pathogens were used to develop a procedure by which our PCLs could reversibly and precisely control SDH utilizing green light. This research would help us to understand the target-ligand interactions and provide new insights into modulation of SDH.
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Affiliation(s)
- Wen Fu
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Zhongli Shao
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Xujuan Sun
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Cong Zhou
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Zhiping Xu
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Yang Zhang
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Jiagao Cheng
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Zhong Li
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China
| | - Xusheng Shao
- Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China
- Shanghai Frontier Science Research Base of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
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17
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Guérineau NC, Campos P, Le Tissier PR, Hodson DJ, Mollard P. Cell Networks in Endocrine/Neuroendocrine Gland Function. Compr Physiol 2022; 12:3371-3415. [PMID: 35578964 DOI: 10.1002/cphy.c210031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Reproduction, growth, stress, and metabolism are determined by endocrine/neuroendocrine systems that regulate circulating hormone concentrations. All these systems generate rhythms and changes in hormone pulsatility observed in a variety of pathophysiological states. Thus, the output of endocrine/neuroendocrine systems must be regulated within a narrow window of effective hormone concentrations but must also maintain a capacity for plasticity to respond to changing physiological demands. Remarkably most endocrinologists still have a "textbook" view of endocrine gland organization which has emanated from 20th century histological studies on thin 2D tissue sections. However, 21st -century technological advances, including in-depth 3D imaging of specific cell types have vastly changed our knowledge. We now know that various levels of multicellular organization can be found across different glands, that organizational motifs can vary between species and can be modified to enhance or decrease hormonal release. This article focuses on how the organization of cells regulates hormone output using three endocrine/neuroendocrine glands that present different levels of organization and complexity: the adrenal medulla, with a single neuroendocrine cell type; the anterior pituitary, with multiple intermingled cell types; and the pancreas with multiple intermingled cell types organized into distinct functional units. We give an overview of recent methodologies that allow the study of the different components within endocrine systems, particularly their temporal and spatial relationships. We believe the emerging findings about network organization, and its impact on hormone secretion, are crucial to understanding how homeostatic regulation of endocrine axes is carried out within endocrine organs themselves. © 2022 American Physiological Society. Compr Physiol 12:3371-3415, 2022.
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Affiliation(s)
| | - Pauline Campos
- College of Engineering, Mathematics and Physical Sciences, University of Exeter, Exeter, UK
| | - Paul R Le Tissier
- Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, Scotland, UK
| | - David J Hodson
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Edgbaston, UK.,Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK.,COMPARE University of Birmingham and University of Nottingham Midlands, UK.,Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), NIHR Oxford Biomedical Research Centre, Churchill Hospital, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Patrice Mollard
- IGF, University of Montpellier, CNRS, INSERM, Montpellier, France
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18
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Mehrpour O, Saeedi F, Hoyte C, Hadianfar A, Nakhaee S, Brent J. Distinguishing characteristics of exposure to biguanide and sulfonylurea anti-diabetic medications in the United States. Am J Emerg Med 2022; 56:171-177. [PMID: 35398707 DOI: 10.1016/j.ajem.2022.03.023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 03/13/2022] [Accepted: 03/13/2022] [Indexed: 01/21/2023] Open
Abstract
OBJECTIVES Biguanides and sulfonylureas are anti-hyperglycemic drugs commonly used in the United States. Poisoning with these drugs may lead to serious consequences. The diagnosis of biguanide and sulfonylurea poisoning is based on history, clinical manifestations, and laboratory studies. METHODS This study is a six-year retrospective cohort analysis based on the National Poison Data System. Clinical effects of 6183 biguanide and sulfonylurea exposures were identified using binary logistic regression. RESULTS The mean age of patients with biguanide and sulfonylurea exposure was 39.27 ± 28.91 and 28.91 ± 30.41 years, respectively. Sulfonylurea exposure is most commonly seen via unintentional exposure, while biguanide exposure frequently occurs as a result of intentional ingestion. Minor and moderate outcomes commonly developed following biguanide and sulfonylurea exposure, respectively. Sulfonylurea exposure was less likely to develop clinical effects abdominal pain, metabolic acidosis, diarrhea, nausea, vomiting, and elevated creatinine than patients ingesting biguanides. However, sulfonylurea exposure was more likely to cause dizziness or vertigo, tremor, drowsiness or lethargy, agitation, diaphoresis, and hypoglycemia. CONCLUSIONS Our study is the first to use a wide range of national data to describe the clinical characteristics that differentiate the toxicologic exposure to biguanides and sulfonylureas. Sulfonylurea exposure is commonly seen via unintentional exposure, while metformin exposure is frequently seen via intentional exposure. Sulfonylurea toxicity is more likely to cause agitation, dizziness or vertigo, tremor, diaphoresis, and hypoglycemia, while metformin exposure induces abdominal pain, acidosis, diarrhea, nausea, vomiting, and elevated creatinine.
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Affiliation(s)
- Omid Mehrpour
- Data Science Institute, Southern Methodist University, Dallas, TX, USA.
| | - Farhad Saeedi
- Medical Toxicology and Drug Abuse Research Center (MTDRC), Birjand University of Medical Sciences, Birjand, Iran; Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran
| | - Christopher Hoyte
- University of Colorado, Anschutz Medical Campus, Aurora, CO, USA; University of Colorado Hospital, Aurora, CO, USA
| | - Ali Hadianfar
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Biostatistics, School of Health, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Samaneh Nakhaee
- Medical Toxicology and Drug Abuse Research Center (MTDRC), Birjand University of Medical Sciences, Birjand, Iran
| | - Jeffrey Brent
- School of Medicine, University of Colorado, Aurora, CO, USA
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19
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Walczewska-Szewc K, Nowak W. Photo-Switchable Sulfonylureas Binding to ATP-Sensitive Potassium Channel Reveal the Mechanism of Light-Controlled Insulin Release. J Phys Chem B 2021; 125:13111-13121. [PMID: 34825567 PMCID: PMC8667036 DOI: 10.1021/acs.jpcb.1c07292] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 11/13/2021] [Indexed: 11/29/2022]
Abstract
ATP-sensitive potassium (KATP) channels are present in numerous organs, including the heart, brain, and pancreas. Physiological opening and closing of KATPs present in pancreatic β-cells, in response to changes in the ATP/ADP concentration ratio, are correlated with insulin release into the bloodstream. Sulfonylurea drugs, commonly used in type 2 diabetes mellitus treatment, bind to the octamer KATP channels composed of four pore-forming Kir6.2 and four SUR1 subunits and increase the probability of insulin release. Azobenzene-based derivatives of sulfonylureas, such as JB253 inspired by well-established antidiabetic drug glimepiride, allow for control of this process by light. The mechanism of that phenomenon was not known until now. In this paper, we use molecular docking, molecular dynamics, and metadynamics to reveal structural determinants explaining light-controlled insulin release. We show that both trans- and cis-JB253 bind to the same SUR1 cavity as antidiabetic sulfonylurea glibenclamide (GBM). Simulations indicate that, in contrast to trans-JB253, the cis-JB253 structure generated by blue light absorption promotes open structures of SUR1, in close similarity to the GBM effect. We postulate that in the open SUR1 structures, the N-terminal tail from Kir6.2 protruding into the SUR1 pocket is stabilized by flexible enough sulfonylureas. Therefore, the adjacent Kir6.2 pore is more often closed, which in turn facilitates insulin release. Thus, KATP conductance is regulated by peptide linkers between its Kir6.2 and SUR1 subunits, a phenomenon present in other biological signaling pathways. Our data explain the observed light-modulated activity of photoactive sulfonylureas and widen a way to develop new antidiabetic drugs having reduced adverse effects.
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Affiliation(s)
- Katarzyna Walczewska-Szewc
- Faculty of Physics, Astronomy
and Informatics, Nicolaus Copernicus University
in Torun, ul. Grudziadzka 5, 87-100 Torun, Poland
| | - Wieslaw Nowak
- Faculty of Physics, Astronomy
and Informatics, Nicolaus Copernicus University
in Torun, ul. Grudziadzka 5, 87-100 Torun, Poland
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20
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Photoinstability in active pharmaceutical ingredients: Crystal engineering as a mitigating measure. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY C: PHOTOCHEMISTRY REVIEWS 2021. [DOI: 10.1016/j.jphotochemrev.2021.100455] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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21
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Ferri G, Pesce L, Tesi M, Marchetti P, Cardarelli F. β-Cell Pathophysiology: A Review of Advanced Optical Microscopy Applications. Int J Mol Sci 2021; 22:ijms222312820. [PMID: 34884624 PMCID: PMC8657725 DOI: 10.3390/ijms222312820] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 11/24/2021] [Accepted: 11/24/2021] [Indexed: 11/30/2022] Open
Abstract
β-cells convert glucose (input) resulting in the controlled release of insulin (output), which in turn has the role to maintain glucose homeostasis. β-cell function is regulated by a complex interplay between the metabolic processing of the input, its transformation into second-messenger signals, and final mobilization of insulin-containing granules towards secretion of the output. Failure at any level in this process marks β-cell dysfunction in diabetes, thus making β-cells obvious potential targets for therapeutic purposes. Addressing quantitatively β-cell (dys)function at the molecular level in living samples requires probing simultaneously the spatial and temporal dimensions at the proper resolution. To this aim, an increasing amount of research efforts are exploiting the potentiality of biophysical techniques. In particular, using excitation light in the visible/infrared range, a number of optical-microscopy-based approaches have been tailored to the study of β-cell-(dys)function at the molecular level, either in label-free mode (i.e., exploiting intrinsic autofluorescence of cells) or by the use of organic/genetically-encoded fluorescent probes. Here, relevant examples from the literature are reviewed and discussed. Based on this, new potential lines of development in the field are drawn.
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Affiliation(s)
- Gianmarco Ferri
- NEST Laboratory, Scuola Normale Superiore, Piazza San Silvestro 12, 56127 Pisa, Italy; (G.F.); (L.P.)
| | - Luca Pesce
- NEST Laboratory, Scuola Normale Superiore, Piazza San Silvestro 12, 56127 Pisa, Italy; (G.F.); (L.P.)
| | - Marta Tesi
- Islet Cell Laboratory, Department of Clinical and Experimental Medicine, University of Pisa, 56127 Pisa, Italy; (M.T.); (P.M.)
| | - Piero Marchetti
- Islet Cell Laboratory, Department of Clinical and Experimental Medicine, University of Pisa, 56127 Pisa, Italy; (M.T.); (P.M.)
| | - Francesco Cardarelli
- NEST Laboratory, Scuola Normale Superiore, Piazza San Silvestro 12, 56127 Pisa, Italy; (G.F.); (L.P.)
- Correspondence:
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22
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Abstract
Azobenzenes are archetypal molecules that have a central role in fundamental and applied research. Over the course of almost two centuries, the area of azobenzenes has witnessed great achievements; azobenzenes have evolved from simple dyes to 'little engines' and have become ubiquitous in many aspects of our lives, ranging from textiles, cosmetics, food and medicine to energy and photonics. Despite their long history, azobenzenes continue to arouse academic interest, while being intensively produced for industrial purposes, owing to their rich chemistry, versatile and straightforward design, robust photoswitching process and biodegradability. The development of azobenzenes has stimulated the production of new coloured and light-responsive materials with various applications, and their use continues to expand towards new high-tech applications. In this Review, we highlight the latest achievements in the synthesis of red-light-responsive azobenzenes and the emerging application areas of photopharmacology, photoswitchable adhesives and biodegradable materials for drug delivery. We show how the synthetic versatility and adaptive properties of azobenzenes continue to inspire new research directions, with limits imposed only by one's imagination.
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23
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Volarić J, Szymanski W, Simeth NA, Feringa BL. Molecular photoswitches in aqueous environments. Chem Soc Rev 2021; 50:12377-12449. [PMID: 34590636 PMCID: PMC8591629 DOI: 10.1039/d0cs00547a] [Citation(s) in RCA: 186] [Impact Index Per Article: 46.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Indexed: 12/17/2022]
Abstract
Molecular photoswitches enable dynamic control of processes with high spatiotemporal precision, using light as external stimulus, and hence are ideal tools for different research areas spanning from chemical biology to smart materials. Photoswitches are typically organic molecules that feature extended aromatic systems to make them responsive to (visible) light. However, this renders them inherently lipophilic, while water-solubility is of crucial importance to apply photoswitchable organic molecules in biological systems, like in the rapidly emerging field of photopharmacology. Several strategies for solubilizing organic molecules in water are known, but there are not yet clear rules for applying them to photoswitchable molecules. Importantly, rendering photoswitches water-soluble has a serious impact on both their photophysical and biological properties, which must be taken into consideration when designing new systems. Altogether, these aspects pose considerable challenges for successfully applying molecular photoswitches in aqueous systems, and in particular in biologically relevant media. In this review, we focus on fully water-soluble photoswitches, such as those used in biological environments, in both in vitro and in vivo studies. We discuss the design principles and prospects for water-soluble photoswitches to inspire and enable their future applications.
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Affiliation(s)
- Jana Volarić
- Centre for Systems Chemistry, Stratingh Institute for Chemistry, Faculty for Science and Engineering, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands.
| | - Wiktor Szymanski
- Centre for Systems Chemistry, Stratingh Institute for Chemistry, Faculty for Science and Engineering, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands.
- Department of Radiology, Medical Imaging Center, University of Groningen, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - Nadja A Simeth
- Centre for Systems Chemistry, Stratingh Institute for Chemistry, Faculty for Science and Engineering, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands.
- Institute for Organic and Biomolecular Chemistry, University of Göttingen, Tammannstr. 2, 37077 Göttingen, Germany
| | - Ben L Feringa
- Centre for Systems Chemistry, Stratingh Institute for Chemistry, Faculty for Science and Engineering, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands.
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24
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Optical Fibre-Enabled Photoswitching for Localised Activation of an Anti-Cancer Therapeutic Drug. Int J Mol Sci 2021; 22:ijms221910844. [PMID: 34639185 PMCID: PMC8509559 DOI: 10.3390/ijms221910844] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/01/2021] [Accepted: 10/03/2021] [Indexed: 11/17/2022] Open
Abstract
Local activation of an anti-cancer drug when and where needed can improve selectivity and reduce undesirable side effects. Photoswitchable drugs can be selectively switched between active and inactive states by illumination with light; however, the clinical development of these drugs has been restricted by the difficulty in delivering light deep into tissue where needed. Optical fibres have great potential for light delivery in vivo, but their use in facilitating photoswitching in anti-cancer compounds has not yet been explored. In this paper, a photoswitchable chemotherapeutic is switched using an optical fibre, and the cytotoxicity of each state is measured against HCT-116 colorectal cancer cells. The performance of optical-fibre-enabled photoswitching is characterised through its dose response. The UV–Vis spectra confirm light delivered by an optical fibre effectively enables photoswitching. The activated drug is shown to be twice as effective as the inactive drug in causing cancer cell death, characterised using an MTT assay and fluorescent microscopy. This is the first study in which a photoswitchable anti-cancer compound is switched using an optical fibre and demonstrates the feasibility of using optical fibres to activate photoswitchable drugs for potential future clinical applications.
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25
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Willems S, Morstein J, Hinnah K, Trauner D, Merk D. A Photohormone for Light-Dependent Control of PPARα in Live Cells. J Med Chem 2021; 64:10393-10402. [PMID: 34213899 DOI: 10.1021/acs.jmedchem.1c00810] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Photopharmacology enables the optical control of several biochemical processes using small-molecule photoswitches that exhibit different bioactivities in their cis- and trans-conformations. Such tool compounds allow for high spatiotemporal control of biological signaling, and the approach also holds promise for the development of drug molecules that can be locally activated to reduce target-mediated adverse effects. Herein, we present the expansion of the photopharmacological arsenal to two new members of the peroxisome proliferator-activated receptor (PPAR) family, PPARα and PPARδ. We have developed a set of highly potent PPARα and PPARδ targeting photohormones derived from the weak pan-PPAR agonist GL479 that can be deactivated by light. The photohormone 6 selectively activated PPARα in its trans-conformation with high selectivity over the related PPAR subtypes and was used in live cells to switch PPARα activity on and off in a light- and time-dependent fashion.
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Affiliation(s)
- Sabine Willems
- Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany
| | - Johannes Morstein
- Department of Chemistry, New York University, New York, New York 10003, United States
| | - Konstantin Hinnah
- Department of Chemistry, New York University, New York, New York 10003, United States
| | - Dirk Trauner
- Department of Chemistry, New York University, New York, New York 10003, United States
| | - Daniel Merk
- Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany
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26
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Kolmar T, Büllmann SM, Sarter C, Höfer K, Jäschke A. Development of High-Performance Pyrimidine Nucleoside and Oligonucleotide Diarylethene Photoswitches. Angew Chem Int Ed Engl 2021; 60:8164-8173. [PMID: 33476096 PMCID: PMC8049081 DOI: 10.1002/anie.202014878] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 01/05/2021] [Indexed: 01/17/2023]
Abstract
Nucleosidic and oligonucleotidic diarylethenes (DAEs) are an emerging class of photochromes with high application potential. However, their further development is hampered by the poor understanding of how the chemical structure modulates the photochromic properties. Here we synthesized 26 systematically varied deoxyuridine- and deoxycytidine-derived DAEs and analyzed reaction quantum yields, composition of the photostationary states, thermal and photochemical stability, and reversibility. This analysis identified two high-performance photoswitches with near-quantitative, fully reversible back-and-forth switching and no detectable thermal or photochemical deterioration. When incorporated into an oligonucleotide with the sequence of a promotor, the nucleotides maintained their photochromism and allowed the modulation of the transcription activity of T7 RNA polymerase with an up to 2.4-fold turn-off factor, demonstrating the potential for optochemical control of biological processes.
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Affiliation(s)
- Theresa Kolmar
- Institute of Pharmacy and Molecular BiotechnologyHeidelberg UniversityIm Neuenheimer Feld 36469120HeidelbergGermany
| | - Simon M. Büllmann
- Institute of Pharmacy and Molecular BiotechnologyHeidelberg UniversityIm Neuenheimer Feld 36469120HeidelbergGermany
| | - Christopher Sarter
- Institute of Pharmacy and Molecular BiotechnologyHeidelberg UniversityIm Neuenheimer Feld 36469120HeidelbergGermany
| | - Katharina Höfer
- Institute of Pharmacy and Molecular BiotechnologyHeidelberg UniversityIm Neuenheimer Feld 36469120HeidelbergGermany
| | - Andres Jäschke
- Institute of Pharmacy and Molecular BiotechnologyHeidelberg UniversityIm Neuenheimer Feld 36469120HeidelbergGermany
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27
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Kolmar T, Büllmann SM, Sarter C, Höfer K, Jäschke A. Development of High‐Performance Pyrimidine Nucleoside and Oligonucleotide Diarylethene Photoswitches. Angew Chem Int Ed Engl 2021. [DOI: 10.1002/ange.202014878] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Affiliation(s)
- Theresa Kolmar
- Institute of Pharmacy and Molecular Biotechnology Heidelberg University Im Neuenheimer Feld 364 69120 Heidelberg Germany
| | - Simon M. Büllmann
- Institute of Pharmacy and Molecular Biotechnology Heidelberg University Im Neuenheimer Feld 364 69120 Heidelberg Germany
| | - Christopher Sarter
- Institute of Pharmacy and Molecular Biotechnology Heidelberg University Im Neuenheimer Feld 364 69120 Heidelberg Germany
| | - Katharina Höfer
- Institute of Pharmacy and Molecular Biotechnology Heidelberg University Im Neuenheimer Feld 364 69120 Heidelberg Germany
| | - Andres Jäschke
- Institute of Pharmacy and Molecular Biotechnology Heidelberg University Im Neuenheimer Feld 364 69120 Heidelberg Germany
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28
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Gutzeit VA, Acosta-Ruiz A, Munguba H, Häfner S, Landra-Willm A, Mathes B, Mony J, Yarotski D, Börjesson K, Liston C, Sandoz G, Levitz J, Broichhagen J. A fine-tuned azobenzene for enhanced photopharmacology in vivo. Cell Chem Biol 2021; 28:1648-1663.e16. [PMID: 33735619 DOI: 10.1016/j.chembiol.2021.02.020] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 12/23/2020] [Accepted: 02/23/2021] [Indexed: 12/15/2022]
Abstract
Despite the power of photopharmacology for interrogating signaling proteins, many photopharmacological systems are limited by their efficiency, speed, or spectral properties. Here, we screen a library of azobenzene photoswitches and identify a urea-substituted "azobenzene-400" core that offers bistable switching between cis and trans with improved kinetics, light sensitivity, and a red-shift. We then focus on the metabotropic glutamate receptors (mGluRs), neuromodulatory receptors that are major pharmacological targets. Synthesis of "BGAG12,400," a photoswitchable orthogonal, remotely tethered ligand (PORTL), enables highly efficient, rapid optical agonism following conjugation to SNAP-tagged mGluR2 and permits robust optical control of mGluR1 and mGluR5 signaling. We then produce fluorophore-conjugated branched PORTLs to enable dual imaging and manipulation of mGluRs and highlight their power in ex vivo slice and in vivo behavioral experiments in the mouse prefrontal cortex. Finally, we demonstrate the generalizability of our strategy by developing an improved soluble, photoswitchable pore blocker for potassium channels.
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Affiliation(s)
- Vanessa A Gutzeit
- Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY 10065, USA
| | - Amanda Acosta-Ruiz
- Biochemistry, Cell and Molecular Biology Graduate Program, Weill Cornell Medicine, New York, NY 10065, USA
| | - Hermany Munguba
- Department of Biochemistry, Weill Cornell Medicine, New York, NY 10065, USA
| | - Stephanie Häfner
- Université Cote d'Azur, CNRS, INSERM, iBV, Nice, France; Laboratories of Excellence, Ion Channel Science and Therapeutics, Nice, France
| | - Arnaud Landra-Willm
- Université Cote d'Azur, CNRS, INSERM, iBV, Nice, France; Laboratories of Excellence, Ion Channel Science and Therapeutics, Nice, France
| | - Bettina Mathes
- Department of Chemical Biology, Max Planck Institute for Medical Research, 69120 Heidelberg, Germany
| | - Jürgen Mony
- Department of Chemistry and Molecular Biology, University of Gothenburg, 41296 Gothenburg, Sweden
| | - Dzianis Yarotski
- Department of Chemical Biology, Max Planck Institute for Medical Research, 69120 Heidelberg, Germany
| | - Karl Börjesson
- Department of Chemistry and Molecular Biology, University of Gothenburg, 41296 Gothenburg, Sweden
| | - Conor Liston
- Department of Psychiatry and Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA
| | - Guillaume Sandoz
- Université Cote d'Azur, CNRS, INSERM, iBV, Nice, France; Laboratories of Excellence, Ion Channel Science and Therapeutics, Nice, France
| | - Joshua Levitz
- Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY 10065, USA; Biochemistry, Cell and Molecular Biology Graduate Program, Weill Cornell Medicine, New York, NY 10065, USA; Department of Biochemistry, Weill Cornell Medicine, New York, NY 10065, USA.
| | - Johannes Broichhagen
- Department of Chemical Biology, Max Planck Institute for Medical Research, 69120 Heidelberg, Germany; Department of Chemical Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, 13125 Berlin, Germany.
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29
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Slor G, Amir RJ. Using High Molecular Precision to Study Enzymatically Induced Disassembly of Polymeric Nanocarriers: Direct Enzymatic Activation or Equilibrium-Based Degradation? Macromolecules 2021; 54:1577-1588. [PMID: 33642615 PMCID: PMC7905880 DOI: 10.1021/acs.macromol.0c02263] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 01/15/2021] [Indexed: 02/01/2023]
Abstract
![]()
Enzyme-responsive polymers and their
assemblies offer great potential
to serve as key materials for the design of drug delivery systems
and other biomedical applications. However, the utilization of enzymes
to trigger the disassembly of polymeric amphiphiles, such as micelles,
also suffers from the limited accessibility of the enzyme to moieties
that are hidden inside the assembled structures. In this Perspective,
we will discuss examples for the utilization of high molecular precision
that dendritic structures offer to study the enzymatic degradation
of polymeric amphiphiles with high resolution. Up to date, several
different amphiphilic systems based on dendritic blocks have all shown
that small changes in the hydrophobicity and amphiphilicity strongly
affected the degree and rate of enzymatic degradation. The ability
to observe the huge effects due to relatively small variations in
the molecular structure of polymers can explain the limited enzymatic
degradation that is often observed for many reported polymeric assemblies.
The observed trends imply that the enzymes cannot reach the hydrophobic
core of the micelles, and instead, they gain access to the amphiphiles
by the unimer–micelle equilibrium, making the unimer exchange
rate a key parameter in tuning the enzymatic degradation rate. Several
approaches that are aimed at overcoming the stability–responsiveness
challenge are discussed as they open the way to the design of stable
and yet enzymatically responsive polymeric nanocarriers.
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Affiliation(s)
- Gadi Slor
- School of Chemistry, Faculty of Exact Sciences, Tel-Aviv University, Tel-Aviv 6997801, Israel.,Tel Aviv University Center for Nanoscience and Nanotechnology, Tel-Aviv University, Tel-Aviv 6997801, Israel
| | - Roey J Amir
- School of Chemistry, Faculty of Exact Sciences, Tel-Aviv University, Tel-Aviv 6997801, Israel.,Tel Aviv University Center for Nanoscience and Nanotechnology, Tel-Aviv University, Tel-Aviv 6997801, Israel.,Blavatnik Center for Drug Discovery, Tel-Aviv University, Tel-Aviv 6997801, Israel.,ADAMA Center for Novel Delivery Systems in Crop Protection, Tel-Aviv University, Tel-Aviv 6997801, Israel.,The Center For Physics And Chemistry Of Living Systems, Tel-Aviv University, Tel-Aviv 6997801, Israel
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30
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Belikov MY, Ievlev MY, Bardasov IN. A novel water-soluble multicolor halo- and photochromic switching system based on a nitrile-rich acceptor. NEW J CHEM 2021. [DOI: 10.1039/d1nj01046h] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
The first example of a multicolor nitrile-rich dye exhibiting pH-tunable negative photochromism and photoacidity in aqueous media under irradiation using visible light was described.
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31
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Frank JA, Antonini MJ, Chiang PH, Canales A, Konrad DB, Garwood IC, Rajic G, Koehler F, Fink Y, Anikeeva P. In Vivo Photopharmacology Enabled by Multifunctional Fibers. ACS Chem Neurosci 2020; 11:3802-3813. [PMID: 33108719 DOI: 10.1021/acschemneuro.0c00577] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Photoswitchable ligands can add an optical switch to a target receptor or signaling cascade and enable reversible control of neural circuits. The application of this approach, termed photopharmacology, to behavioral experiments has been impeded by a lack of integrated hardware capable of delivering both light and compounds to deep brain regions in moving subjects. Here, we devise a hybrid photochemical genetic approach to target neurons using a photoswitchable agonist of the capsaicin receptor TRPV1, red-AzCA-4. Using multifunctional fibers with optical and microfluidic capabilities, we delivered a transgene coding for TRPV1 into the ventral tegmental area (VTA). This sensitized excitatory VTA neurons to red-AzCA-4, allowing us to optically control conditioned place preference in mice, thus extending applications of photopharmacology to behavioral experiments. Applied to endogenous receptors, our approach may accelerate future studies of molecular mechanisms underlying animal behavior.
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Affiliation(s)
- James A. Frank
- Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Vollum Institute, Oregon Health & Science University, Portland, Oregon 97239, United States
| | - Marc-Joseph Antonini
- Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Harvard/MIT Health Science & Technology Graduate Program, Cambridge, Massachusetts 02139, United States
| | - Po-Han Chiang
- Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Institute of Biomedical Engineering, National Chiao Tung University, Hsinchu 300, Taiwan (R.O.C.)
| | - Andres Canales
- Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
| | - David B. Konrad
- Department of Pharmacy, Ludwig Maximilian University, D-81377 Munich, Germany
| | - Indie C. Garwood
- Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Harvard/MIT Health Science & Technology Graduate Program, Cambridge, Massachusetts 02139, United States
| | - Gabriela Rajic
- Vollum Institute, Oregon Health & Science University, Portland, Oregon 97239, United States
| | - Florian Koehler
- Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
| | - Yoel Fink
- Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
| | - Polina Anikeeva
- Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
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32
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Klaja O, Frank JA, Trauner D, Bondar AN. Potential energy function for a photo-switchable lipid molecule. J Comput Chem 2020; 41:2336-2351. [PMID: 32749723 DOI: 10.1002/jcc.26387] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 05/07/2020] [Accepted: 07/04/2020] [Indexed: 11/06/2022]
Abstract
Photo-switchable lipids are synthetic lipid molecules used in photo-pharmacology to alter membrane lateral pressure and thus control opening and closing of mechanosensitive ion channels. The molecular picture of how photo-switchable lipids interact with membranes or ion channels is poorly understood. To facilitate all-atom simulations that could provide a molecular picture of membranes with photo-switchable lipids, we derived force field parameters for atomistic computations of the azobenzene-based fatty acid FAAzo-4. We implemented a Phyton-based algorithm to make the optimization of atomic partial charges more efficient. Overall, the parameters we derived give good description of the equilibrium structure, torsional properties, and non-bonded interactions for the photo-switchable lipid in its trans and cis intermediate states, and crystal lattice parameters for trans-FAAzo-4. These parameters can be extended to all-atom descriptions of various photo-switchable lipids that have an azobenzene moiety.
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Affiliation(s)
- Oskar Klaja
- Department of Physics, Theoretical Molecular Biophysics Group, Freie Universität Berlin, Berlin, Germany
| | - James A Frank
- Vollum Institute, Oregon Health & Science University, Portland, Oregon, USA
| | - Dirk Trauner
- Department of Chemistry, New York University, New York, New York, USA
| | - Ana-Nicoleta Bondar
- Department of Physics, Theoretical Molecular Biophysics Group, Freie Universität Berlin, Berlin, Germany
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33
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Huey J, Keutler K, Schultz C. Chemical Biology Toolbox for Studying Pancreatic Islet Function - A Perspective. Cell Chem Biol 2020; 27:1015-1031. [PMID: 32822616 DOI: 10.1016/j.chembiol.2020.07.023] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 07/10/2020] [Accepted: 07/28/2020] [Indexed: 01/14/2023]
Abstract
The islets of Langerhans represent one of the many complex endocrine organs in mammals. Traditionally, islet function is studied by a mixture of physiological, cell biological, and molecular biological methods. Recently, novel techniques stemming from the ever-increasing toolbox provided by chemical laboratories have been added to the repertoire. Many emerging techniques will soon be available to manipulate and monitor islet function at the single-cell level and potentially in intact model animals, as well as in isolated human islets. Here, we review the most current small-molecule-based and genetically encoded molecular tool sets available to study islet function. We provide an outlook regarding future tool developments that will impact islet research, with a special focus on the interplay between different islet cell types.
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Affiliation(s)
- Julia Huey
- Program in Physiology and Pharmacology, Oregon Health and Science University, Portland, OR 97210, USA; Department of Chemical Physiology and Biochemistry, Oregon Health and Science University, Portland, OR 97210, USA
| | - Kaya Keutler
- Program in Physiology and Pharmacology, Oregon Health and Science University, Portland, OR 97210, USA; Department of Chemical Physiology and Biochemistry, Oregon Health and Science University, Portland, OR 97210, USA
| | - Carsten Schultz
- Department of Chemical Physiology and Biochemistry, Oregon Health and Science University, Portland, OR 97210, USA.
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Yang X, Ma G, Zheng S, Qin X, Li X, Du L, Wang Y, Zhou Y, Li M. Optical Control of CRAC Channels Using Photoswitchable Azopyrazoles. J Am Chem Soc 2020; 142:9460-9470. [DOI: 10.1021/jacs.0c02949] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Affiliation(s)
- Xingye Yang
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, School of Pharmacy, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Guolin Ma
- Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, Texas 77030, United States
| | - Sisi Zheng
- Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Xiaojun Qin
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, School of Pharmacy, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Xiang Li
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, School of Pharmacy, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Lupei Du
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, School of Pharmacy, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
| | - Youjun Wang
- Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Yubin Zhou
- Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, Texas 77030, United States
| | - Minyong Li
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, School of Pharmacy, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China
- Helmholtz International Lab, State Key Laboratory of Microbial Technology, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250100, China
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Paoletti P, Ellis-Davies GCR, Mourot A. Optical control of neuronal ion channels and receptors. Nat Rev Neurosci 2020; 20:514-532. [PMID: 31289380 DOI: 10.1038/s41583-019-0197-2] [Citation(s) in RCA: 126] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Light-controllable tools provide powerful means to manipulate and interrogate brain function with relatively low invasiveness and high spatiotemporal precision. Although optogenetic approaches permit neuronal excitation or inhibition at the network level, other technologies, such as optopharmacology (also known as photopharmacology) have emerged that provide molecular-level control by endowing light sensitivity to endogenous biomolecules. In this Review, we discuss the challenges and opportunities of photocontrolling native neuronal signalling pathways, focusing on ion channels and neurotransmitter receptors. We describe existing strategies for rendering receptors and channels light sensitive and provide an overview of the neuroscientific insights gained from such approaches. At the crossroads of chemistry, protein engineering and neuroscience, optopharmacology offers great potential for understanding the molecular basis of brain function and behaviour, with promises for future therapeutics.
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Affiliation(s)
- Pierre Paoletti
- Institut de Biologie de l'Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, CNRS, INSERM, Université PSL, Paris, France.
| | | | - Alexandre Mourot
- Neuroscience Paris Seine-Institut de Biologie Paris Seine (NPS-IBPS), CNRS, INSERM, Sorbonne Université, Paris, France.
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Camarero N, Trapero A, Pérez-Jiménez A, Macia E, Gomila-Juaneda A, Martín-Quirós A, Nevola L, Llobet A, Llebaria A, Hernando J, Giralt E, Gorostiza P. Photoswitchable dynasore analogs to control endocytosis with light. Chem Sci 2020. [DOI: 10.1039/d0sc03820b] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
We've combined the pharmacological properties of the dynamin inhibitor dynasore and the photochromic properties of an azobenzene group, to obtain the first light-regulated small-molecule inhibitor of endocytosis.
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Affiliation(s)
- Núria Camarero
- Institute for Bioengineering of Catalonia (IBEC)
- The Barcelona Institute of Science and Technology (BIST)
- Spain
| | - Ana Trapero
- Institute for Bioengineering of Catalonia (IBEC)
- The Barcelona Institute of Science and Technology (BIST)
- Spain
- Institute for Advanced Chemistry of Catalonia (IQAC-CSIC)
- Spain
| | - Ariadna Pérez-Jiménez
- Institute for Bioengineering of Catalonia (IBEC)
- The Barcelona Institute of Science and Technology (BIST)
- Spain
| | - Eric Macia
- Institut de Pharmacologie Moléculaire et Cellulaire (IPMC)
- Université Nice Sophia Antipolis
- France
| | - Alexandre Gomila-Juaneda
- Institute for Bioengineering of Catalonia (IBEC)
- The Barcelona Institute of Science and Technology (BIST)
- Spain
| | - Andrés Martín-Quirós
- Institute for Bioengineering of Catalonia (IBEC)
- The Barcelona Institute of Science and Technology (BIST)
- Spain
| | - Laura Nevola
- Institute for Research in Biomedicine (IRB Barcelona)
- Spain
| | - Artur Llobet
- Bellvitge Biomedical Research Institute (IDIBELL)
- Spain
| | - Amadeu Llebaria
- Institute for Advanced Chemistry of Catalonia (IQAC-CSIC)
- Spain
| | - Jordi Hernando
- Departament de Química
- Universitat Autònoma de Barcelona (UAB)
- Spain
| | - Ernest Giralt
- Institute for Research in Biomedicine (IRB Barcelona)
- Spain
- Universitat de Barcelona (UB)
- Spain
| | - Pau Gorostiza
- Institute for Bioengineering of Catalonia (IBEC)
- The Barcelona Institute of Science and Technology (BIST)
- Spain
- CIBER-BBN
- Spain
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Bridge T, Shaikh SA, Thomas P, Botta J, McCormick PJ, Sachdeva A. Site-Specific Encoding of Photoactivity in Antibodies Enables Light-Mediated Antibody-Antigen Binding on Live Cells. Angew Chem Int Ed Engl 2019; 58:17986-17993. [PMID: 31609054 PMCID: PMC6973043 DOI: 10.1002/anie.201908655] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 09/11/2019] [Indexed: 12/20/2022]
Abstract
Antibodies have found applications in several fields, including, medicine, diagnostics, and nanotechnology, yet methods to modulate antibody-antigen binding using an external agent remain limited. Here, we have developed photoactive antibody fragments by genetic site-specific replacement of single tyrosine residues with photocaged tyrosine, in an antibody fragment, 7D12. A simple and robust assay is adopted to evaluate the light-mediated binding of 7D12 mutants to its target, epidermal growth factor receptor (EGFR), on the surface of cancer cells. Presence of photocaged tyrosine reduces 7D12-EGFR binding affinity by over 20-fold in two out of three 7D12 mutants studied, and binding is restored upon exposure to 365 nm light. Molecular dynamics simulations explain the difference in effect of photocaging on 7D12-EGFR interaction among the mutants. Finally, we demonstrate the application of photoactive antibodies in delivering fluorophores to EGFR-positive live cancer cells in a light-dependent manner.
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Affiliation(s)
- Thomas Bridge
- School of ChemistryUniversity of East AngliaNorwichNR4 7TJUK
| | - Saher A. Shaikh
- School of ChemistryUniversity of East AngliaNorwichNR4 7TJUK
| | - Paul Thomas
- The Henry Wellcome Laboratory of Cell ImagingUniversity of East AngliaNorwichNR4 7TJUK
| | - Joaquin Botta
- Centre of EndocrinologyWilliam Harvey Research InstituteQueen Mary University LondonCharterhouse SquareLondonEC1M 6BQUK
| | - Peter J. McCormick
- Centre of EndocrinologyWilliam Harvey Research InstituteQueen Mary University LondonCharterhouse SquareLondonEC1M 6BQUK
| | - Amit Sachdeva
- School of ChemistryUniversity of East AngliaNorwichNR4 7TJUK
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Kawahara B, Gao L, Cohn W, Whitelegge JP, Sen S, Janzen C, Mascharak PK. Diminished viability of human ovarian cancer cells by antigen-specific delivery of carbon monoxide with a family of photoactivatable antibody-photoCORM conjugates. Chem Sci 2019; 11:467-473. [PMID: 32190266 PMCID: PMC7067254 DOI: 10.1039/c9sc03166a] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 11/18/2019] [Indexed: 12/12/2022] Open
Abstract
Antibodies conjugated to a photoactive transition metal carbonyl complex afford antigen-directed delivery of cytotoxic carbon monoxide to ovarian cancer cells.
Carbon monoxide (CO)-releasing antibody conjugates were synthesized utilizing a photoactivatable CO-releasing molecule (photoCORM) and mouse monoclonal antibodies linked by a biotin-streptavidin system. Different monoclonal antibodies raised against different surface-expressed antigens that are implicated in ovarian cancer afforded a family of antibody-photoCORM conjugates (Ab-photoCORMs). In an immunosorbent/cell viability assay, Ab-photoCORMs accumulated onto ovarian cancer cells expressing the target antigens, delivering cytotoxic doses of CO in vitro. The results described here provide the first example of an “immunoCORM”, a proof-of-the-concept antibody-drug conjugate that delivers a gaseous molecule as a warhead to ovarian cancer.
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Affiliation(s)
- Brian Kawahara
- Department of Chemistry and Biochemistry , University of California , Santa Cruz , CA 95064 , USA .
| | - Lucy Gao
- Pasarow Mass Spectrometry Laboratory , Jane and Terry Semel Institute for Neuroscience and Human Behavior , University of California at Los Angeles , Los Angeles , CA 90095 , USA
| | - Whitaker Cohn
- Pasarow Mass Spectrometry Laboratory , Jane and Terry Semel Institute for Neuroscience and Human Behavior , University of California at Los Angeles , Los Angeles , CA 90095 , USA
| | - Julian P Whitelegge
- Pasarow Mass Spectrometry Laboratory , Jane and Terry Semel Institute for Neuroscience and Human Behavior , University of California at Los Angeles , Los Angeles , CA 90095 , USA
| | - Suvajit Sen
- Department of Obstetrics and Gynecology , David Geffen School of Medicine , University of California at Los Angeles , Los Angeles , CA 90095 , USA
| | - Carla Janzen
- Department of Obstetrics and Gynecology , David Geffen School of Medicine , University of California at Los Angeles , Los Angeles , CA 90095 , USA
| | - Pradip K Mascharak
- Department of Chemistry and Biochemistry , University of California , Santa Cruz , CA 95064 , USA .
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Bridge T, Shaikh SA, Thomas P, Botta J, McCormick PJ, Sachdeva A. Site‐Specific Encoding of Photoactivity in Antibodies Enables Light‐Mediated Antibody–Antigen Binding on Live Cells. Angew Chem Int Ed Engl 2019. [DOI: 10.1002/ange.201908655] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Thomas Bridge
- School of ChemistryUniversity of East Anglia Norwich NR4 7TJ UK
| | - Saher A. Shaikh
- School of ChemistryUniversity of East Anglia Norwich NR4 7TJ UK
| | - Paul Thomas
- The Henry Wellcome Laboratory of Cell ImagingUniversity of East Anglia Norwich NR4 7TJ UK
| | - Joaquin Botta
- Centre of EndocrinologyWilliam Harvey Research InstituteQueen Mary University London Charterhouse Square London EC1M 6BQ UK
| | - Peter J. McCormick
- Centre of EndocrinologyWilliam Harvey Research InstituteQueen Mary University London Charterhouse Square London EC1M 6BQ UK
| | - Amit Sachdeva
- School of ChemistryUniversity of East Anglia Norwich NR4 7TJ UK
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Trads JB, Hüll K, Matsuura BS, Laprell L, Fehrentz T, Görldt N, Kozek KA, Weaver CD, Klöcker N, Barber DM, Trauner D. Sign Inversion in Photopharmacology: Incorporation of Cyclic Azobenzenes in Photoswitchable Potassium Channel Blockers and Openers. Angew Chem Int Ed Engl 2019. [DOI: 10.1002/ange.201905790] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Julie B. Trads
- Department of Chemistry and Center for Integrated Protein Science (CIPSM) Ludwig Maximilian University Munich Butenandtstr. 5–13 81377 Munich Germany
- Center for DNA Nanotechnology Department of Chemistry and iNANO Aarhus University Gustav Wieds Vej 14 8000 Aarhus C Denmark
| | - Katharina Hüll
- Department of Chemistry and Center for Integrated Protein Science (CIPSM) Ludwig Maximilian University Munich Butenandtstr. 5–13 81377 Munich Germany
- Department of Chemistry New York University 100 Washington Square East New York NY 10003-6699 USA
| | - Bryan S. Matsuura
- Department of Chemistry and Center for Integrated Protein Science (CIPSM) Ludwig Maximilian University Munich Butenandtstr. 5–13 81377 Munich Germany
- Department of Chemistry New York University 100 Washington Square East New York NY 10003-6699 USA
| | - Laura Laprell
- Department of Chemistry and Center for Integrated Protein Science (CIPSM) Ludwig Maximilian University Munich Butenandtstr. 5–13 81377 Munich Germany
| | - Timm Fehrentz
- Institute of Neural and Sensory Physiology, Medical Faculty University of Düsseldorf Düsseldorf Germany
| | - Nicole Görldt
- Institute of Neural and Sensory Physiology, Medical Faculty University of Düsseldorf Düsseldorf Germany
| | - Krystian A. Kozek
- Department of Pharmacology Vanderbilt University School of Medicine Nashville TN USA
| | - C. David Weaver
- Departments of Pharmacology and Chemistry Institute of Chemical Biology Vanderbilt University School of Medicine Nashville TN USA
| | - Nikolaj Klöcker
- Institute of Neural and Sensory Physiology, Medical Faculty University of Düsseldorf Düsseldorf Germany
| | - David M. Barber
- Department of Chemistry and Center for Integrated Protein Science (CIPSM) Ludwig Maximilian University Munich Butenandtstr. 5–13 81377 Munich Germany
| | - Dirk Trauner
- Department of Chemistry and Center for Integrated Protein Science (CIPSM) Ludwig Maximilian University Munich Butenandtstr. 5–13 81377 Munich Germany
- Department of Chemistry New York University 100 Washington Square East New York NY 10003-6699 USA
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Trads JB, Hüll K, Matsuura BS, Laprell L, Fehrentz T, Görldt N, Kozek KA, Weaver CD, Klöcker N, Barber DM, Trauner D. Sign Inversion in Photopharmacology: Incorporation of Cyclic Azobenzenes in Photoswitchable Potassium Channel Blockers and Openers. Angew Chem Int Ed Engl 2019; 58:15421-15428. [PMID: 31441199 DOI: 10.1002/anie.201905790] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 07/30/2019] [Indexed: 01/22/2023]
Abstract
Photopharmacology relies on ligands that change their pharmacodynamics upon photoisomerization. Many of these ligands are azobenzenes that are thermodynamically more stable in their elongated trans-configuration. Often, they are biologically active in this form and lose activity upon irradiation and photoisomerization to their cis-isomer. Recently, cyclic azobenzenes, so-called diazocines, have emerged, which are thermodynamically more stable in their bent cis-form. Incorporation of these switches into a variety of photopharmaceuticals could convert dark-active ligands into dark-inactive ligands, which is preferred in most biological applications. This "pharmacological sign-inversion" is demonstrated for a photochromic blocker of voltage-gated potassium channels, termed CAL, and a photochromic opener of G protein-coupled inwardly rectifying potassium (GIRK) channels, termed CLOGO.
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Affiliation(s)
- Julie B Trads
- Department of Chemistry and Center for Integrated Protein Science (CIPSM), Ludwig Maximilian University Munich, Butenandtstr. 5-13, 81377, Munich, Germany.,Center for DNA Nanotechnology, Department of Chemistry and iNANO, Aarhus University, Gustav Wieds Vej 14, 8000, Aarhus C, Denmark
| | - Katharina Hüll
- Department of Chemistry and Center for Integrated Protein Science (CIPSM), Ludwig Maximilian University Munich, Butenandtstr. 5-13, 81377, Munich, Germany.,Department of Chemistry, New York University, 100 Washington Square East, New York, NY, 10003-6699, USA
| | - Bryan S Matsuura
- Department of Chemistry and Center for Integrated Protein Science (CIPSM), Ludwig Maximilian University Munich, Butenandtstr. 5-13, 81377, Munich, Germany.,Department of Chemistry, New York University, 100 Washington Square East, New York, NY, 10003-6699, USA
| | - Laura Laprell
- Department of Chemistry and Center for Integrated Protein Science (CIPSM), Ludwig Maximilian University Munich, Butenandtstr. 5-13, 81377, Munich, Germany
| | - Timm Fehrentz
- Institute of Neural and Sensory Physiology, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany
| | - Nicole Görldt
- Institute of Neural and Sensory Physiology, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany
| | - Krystian A Kozek
- Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - C David Weaver
- Departments of Pharmacology and Chemistry, Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Nikolaj Klöcker
- Institute of Neural and Sensory Physiology, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany
| | - David M Barber
- Department of Chemistry and Center for Integrated Protein Science (CIPSM), Ludwig Maximilian University Munich, Butenandtstr. 5-13, 81377, Munich, Germany
| | - Dirk Trauner
- Department of Chemistry and Center for Integrated Protein Science (CIPSM), Ludwig Maximilian University Munich, Butenandtstr. 5-13, 81377, Munich, Germany.,Department of Chemistry, New York University, 100 Washington Square East, New York, NY, 10003-6699, USA
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Albert L, Vázquez O. Photoswitchable peptides for spatiotemporal control of biological functions. Chem Commun (Camb) 2019; 55:10192-10213. [PMID: 31411602 DOI: 10.1039/c9cc03346g] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Light is unsurpassed in its ability to modulate biological interactions. Since their discovery, chemists have been fascinated by photosensitive molecules capable of switching between isomeric forms, known as photoswitches. Photoswitchable peptides have been recognized for many years; however, their functional implementation in biological systems has only recently been achieved. Peptides are now acknowledged as excellent protein-protein interaction modulators and have been important in the emergence of photopharmacology. In this review, we briefly explain the different classes of photoswitches and summarize structural studies when they are incorporated into peptides. Importantly, we provide a detailed overview of the rapidly increasing number of examples, where biological modulation is driven by the structural changes. Furthermore, we discuss some of the remaining challenges faced in this field. These exciting proof-of-principle studies highlight the tremendous potential of photocontrollable peptides as optochemical tools for chemical biology and biomedicine.
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Affiliation(s)
- Lea Albert
- Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Straße 4, 35043, Marburg, Germany.
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Li Z, Wang Y, Li M, Zhang H, Guo H, Ya H, Yin J. Synthesis and properties of dithienylethene-functionalized switchable antibacterial agents. Org Biomol Chem 2019; 16:6988-6997. [PMID: 30229787 DOI: 10.1039/c8ob01824c] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Photopharmacology involving azobenzene has offered a viable alternative for combating bacterial resistance. However, the degradation and potential toxicity of azobenzene limit its further study in vivo. Therefore, searching for an appropriate photoswitch for further clinical application is highly desirable. Herein a series of dithienylethene-functionalized switchable antibacterial agents have been designed and prepared by the introduction of the dithienylethene scaffold into fluoroquinolones. And it was found that these switchable antibacterial agents displayed good photochromism and fluorescence switching behaviors upon irradiation with UV/Vis light in DMSO. Surprisingly, methoxy-substituted dithienylethenes 3a and 3b exhibited fluorescence turn-on behavior. Furthermore, it was found that all of the open-isomers showed partial antibacterial activity on E. coli and S. aureus compared with the native drugs. Apart from 2a and 2b, the other switchable antibacterial agents showed a large difference in antibacterial activity on Gram-negative E. coli between the open and closed forms, in which the antimicrobial activity of the ring-closed isomers for 1b and 3b was 16 times that of the corresponding ring-open isomers. DFT calculations showed that the ring-closed isomers of 1b and 3b presented a rigid "S-type" conformation, which may be conducive to forming more stable complexes with the DNA gyrase of E. coli.
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Affiliation(s)
- Ziyong Li
- Key Laboratory of Organic Functional Molecules, Luoyang City, College of Food and Drug, Luoyang Normal University, Luoyang 471934, P. R. China.
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Yuan YX, Zheng YS. New Acylhydrazone Photoswitches with Quantitative Conversion and High Quantum Yield but without Hydrogen Bond Stabilizing ( Z)-Isomer. ACS APPLIED MATERIALS & INTERFACES 2019; 11:7303-7310. [PMID: 30675784 DOI: 10.1021/acsami.8b21719] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Hydrazones are recently attracting increasing interest because of their facile synthesis and high addressability, fatigue resistance, and modifiability as molecular switches. However, this new class of switches generally suffers from low conversion from E- to Z-configuration. Here, novel benzoylhydrazones were synthesized by condensation of 2-methoxynaphthaldhyde and benzoylhydrazine. In this hydrazone system, both sides of the imine double bond had large steric hindrance, so that the ( E)-isomer of the benzoylhydrazones was less stable and easily converted into the ( Z)-isomer even without an intramolecular hydrogen bond. Up to 99% conversion efficiency and 89% quantum yield were obtained, in addition to excellent addressability and high fatigue resistance. Outstandingly, the crystal structure of one ( Z)-isomer disclosed no intermolecular hydrogen bonds between the molecules of the ( Z)-isomer but strong and sequential hydrogen bonds between those of the ( E)-isomer. Therefore, the ( E)-isomer was less soluble in solvents than the ( Z)-isomer. This molecular switch system could be easily modified by both hydrophilic pentaethylene glycol chains and hydrophobic octyl chains. Under light irradiation, the resultant amphiphilic acylhydrazone could be transferred from ( E)-isomer to ( Z)-isomer in more than 90% yield even in water after light irradiation. Meanwhile, the self-assembled big nanospheres could rearrange into much smaller vesicles because of the solubility difference of ( Z)- and ( E)-isomers. After the anticancer drug procarbazine was loaded by this kind of acylhydrazone in water, it could be released by light irradiation, showing potential application in photocontrollable drug release.
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Affiliation(s)
- Ying-Xue Yuan
- Key Laboratory of Material Chemistry for Energy Conversion and Storage, Ministry of Education, School of Chemistry and Chemical Engineering , Huazhong University of Science and Technology , Wuhan 430074 , China
| | - Yan-Song Zheng
- Key Laboratory of Material Chemistry for Energy Conversion and Storage, Ministry of Education, School of Chemistry and Chemical Engineering , Huazhong University of Science and Technology , Wuhan 430074 , China
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Prihatin J, Narulita E, Mufidah L, Kurniawan A, Wulandari D, Hariyadi S. Antihyperglycaemic and tissue-repair effects of Myrmeleon formicarius extract in streptozotocin-induced diabetic mice. J Taibah Univ Med Sci 2019; 14:149-155. [PMID: 31435405 PMCID: PMC6694966 DOI: 10.1016/j.jtumed.2019.01.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 01/12/2019] [Accepted: 01/20/2019] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVES In this study, we aimed to investigate the effects of oral administration of Myrmeleon formicarius (antlion) extract on liver and kidney histology in streptozotocin-induced diabetic mice. METHODS Twenty-four mice received a single intraperitoneal injection of streptozotocin and were then divided into six groups. Untreated diabetic mice served as the negative control group, and glibenclamide-treated mice served as the positive control group. Mice in the other four groups, namely T1, T2, T3, and T4 groups, received M. formicarius (antlion) extract at 2.5, 5, 7.5, and 10 mg/kg, respectively. Permanent thin sections were used to examine liver and kidney histology. RESULTS The most appropriate antihyperglycaemic dosage of the M. formicarius extract was 10 mg/kg for 2 days. Histological examination of the liver and kidneys showed that the antlion extract at 10 and 5 mg/kg exhibited significant tissue-repair effects. CONCLUSION M. formicarius (antlion) extract can not only reduce blood glucose levels but also repair hyperglycaemia-induced tissue damage.
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Affiliation(s)
- Jekti Prihatin
- Department of Biology Education, University of Jember, Jember, Indonesia
| | - Erlia Narulita
- Department of Biology Education, University of Jember, Jember, Indonesia,Corresponding address: Centre for Development of Advance Science and Technology, University of Jember, JL. Kalimantan 37 Kampus Tegalboto, Jember 68121, Indonesia.
| | - Lailatul Mufidah
- Department of Biology Education, University of Jember, Jember, Indonesia
| | - Alief Kurniawan
- Department of Biology Education, University of Jember, Jember, Indonesia
| | - Dwi Wulandari
- Department of Biology Education, University of Jember, Jember, Indonesia
| | - Slamet Hariyadi
- Department of Biology Education, University of Jember, Jember, Indonesia
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Zhou X, Zhang R, Zou Z, Shen X, Xie T, Xu C, Dong J, Liao L. Hypoglycaemic effects of glimepiride in sulfonylurea receptor 1 deficient rat. Br J Pharmacol 2018; 176:478-490. [PMID: 30471094 DOI: 10.1111/bph.14553] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 10/30/2018] [Accepted: 11/02/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND AND PURPOSE Sulfonylureas (SUs) have been suggested to have an insulin-independent blood glucose-decreasing activity due to an extrapancreatic effect. However, a lack of adequate in vivo evidence makes this statement controversial. Here, we aimed to evaluate whether glimepiride has extrapancreatic blood glucose-lowering activity in vivo. EXPERIMENTAL APPROACH Sulfonylurea receptor 1 deficient (SUR1-/- ) rats were created by means of transcription activator-like effector nucleases (TALEN)-mediated gene targeting technology. Type 2 diabetic models were established by feeding a high-fat diet and administering a low-dose of streptozotocin. These rats were then randomly divided into four groups: glimepiride, gliclazide, metformin and saline. All rats were treated for 2 weeks. KEY RESULTS Glimepiride decreased blood glucose levels and increased insulin sensitivity without elevating insulin levels. Gliclazide showed similar effects as glimepiride. Both agents were weaker than metformin. Further mechanistic investigations revealed that glimepiride increased hepatic glycogen synthesis and decreased gluconeogenesis, which were accompanied by the activation of Akt in the liver. Moreover, glimepiride increased both total and membrane glucose transporter 4 (GLUT4) levels in muscle and fat, which might be attributed to insulin receptor-independent IRS1/Akt activation. CONCLUSION AND IMPLICATIONS Glimepiride possesses an extrapancreatic blood glucose-lowering effect in vivo, which might be attributed to its direct effect on insulin-sensitive tissues. Therefore, the combination of glimepiride with multiple insulin injections should not be excluded per se.
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Affiliation(s)
- Xiaojun Zhou
- Department of Endocrinology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China
| | - Rui Zhang
- Department of Endocrinology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China
| | - Zhiwei Zou
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, China
| | - Xue Shen
- Department of Endocrinology, Shandong Provincial Qianfoshan Hospital, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Tianyue Xie
- Department of Endocrinology, Shandong Provincial Qianfoshan Hospital, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Chunmei Xu
- Department of Endocrinology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China
| | - Jianjun Dong
- Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, China
| | - Lin Liao
- Department of Endocrinology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China
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Frank JA, Broichhagen J, Yushchenko DA, Trauner D, Schultz C, Hodson DJ. Optical tools for understanding the complexity of β-cell signalling and insulin release. Nat Rev Endocrinol 2018; 14:721-737. [PMID: 30356209 DOI: 10.1038/s41574-018-0105-2] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Following stimulation, pancreatic β-cells must orchestrate a plethora of signalling events to ensure the appropriate release of insulin and maintenance of normal glucose homeostasis. Failure at any point in this cascade leads to impaired insulin secretion, elevated blood levels of glucose and eventually type 2 diabetes mellitus. Likewise, β-cell replacement or regeneration strategies for the treatment of both type 1 and type 2 diabetes mellitus might fail if the correct cell signalling phenotype cannot be faithfully recreated. However, current understanding of β-cell function is complicated because of the highly dynamic nature of their intracellular and intercellular signalling as well as insulin release itself. β-Cells must precisely integrate multiple signals stemming from multiple cues, often with differing intensities, frequencies and cellular and subcellular localizations, before converging these signals onto insulin exocytosis. In this respect, optical approaches with high resolution in space and time are extremely useful for properly deciphering the complexity of β-cell signalling. An increased understanding of β-cell signalling might identify new mechanisms underlying insulin release, with relevance for future drug therapy and de novo stem cell engineering of functional islets.
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Affiliation(s)
- James A Frank
- Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Johannes Broichhagen
- Department of Chemical Biology, Max Planck Institute for Medical Research, Heidelberg, Germany
| | - Dmytro A Yushchenko
- Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic
| | - Dirk Trauner
- Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Chemistry, New York University, New York, NY, USA
| | - Carsten Schultz
- European Molecular Biology Laboratory (EMBL), Cell Biology and Biophysics Unit, Heidelberg, Germany.
- Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, OR, USA.
| | - David J Hodson
- Institute of Metabolism and Systems Research (IMSR) and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK.
- Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK.
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Spacial models of malfunctioned protein complexes help to elucidate signal transduction critical for insulin release. Biosystems 2018; 177:48-55. [PMID: 30395892 DOI: 10.1016/j.biosystems.2018.11.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Revised: 10/30/2018] [Accepted: 11/01/2018] [Indexed: 12/14/2022]
Abstract
Mutations in gene KCNJ11 encoding the Kir6.2 subunit of the ATP-sensitive potassium channel (KATP), a representative of a quite complex biosystem, may affect insulin release from pancreatic beta-cells. Both gain and loss of channel activity are observed, which lead to varied clinical phenotypes ranging from neonatal diabetes to congenital hyperinsulinism. In order to understand the mechanisms of the channel function better we mapped, based on the literature review, known medically relevant Kir6.2/SUR1 mutations into recently (2017) determined CryoEM 3D structures of this complex. We used a clustering algorithm to find hots spots in the 3D structure, thus we may hypothesize about their nano-mechanical role in the channel gating and the insulin level control. We also adapted a simple model of the channel gating to cover all currently known factors that can influence the KATP biosystem functions.
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Abstract
Molecular motors are Nature's solution for (supra)molecular transport and muscle functioning and are involved in most forms of directional motion at the cellular level. Their synthetic counterparts have also found a myriad of applications, ranging from molecular machines and smart materials to catalysis and anion transport. Although light-driven rotary molecular motors are likely to be suitable for use in an artificial cell, as well as in bionanotechnology, thus far they are not readily applied under physiological conditions. This results mainly from their inherently aromatic core structure, which makes them insoluble in aqueous solution. Here, the study of the dynamic behavior of these motors in biologically relevant media is described. Two molecular motors were equipped with solubilizing substituents and studied in aqueous solutions. Additionally, the behavior of a previously reported molecular motor was studied in micelles, as a model system for the biologically relevant confined environment. Design principles were established for molecular motors in these media, and insights are given into pH-dependent behavior. The work presented herein may provide a basis for the application of the remarkable properties of molecular motors in more advanced biohybrid systems.
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Affiliation(s)
- Anouk S Lubbe
- Center for Systems Chemistry, Stratingh Institute for Chemistry , University of Groningen , Nijenborgh 4 , 9747 AG Groningen , The Netherlands
| | - Christian Böhmer
- Center for Systems Chemistry, Stratingh Institute for Chemistry , University of Groningen , Nijenborgh 4 , 9747 AG Groningen , The Netherlands
| | - Filippo Tosi
- Center for Systems Chemistry, Stratingh Institute for Chemistry , University of Groningen , Nijenborgh 4 , 9747 AG Groningen , The Netherlands
| | - Wiktor Szymanski
- Center for Systems Chemistry, Stratingh Institute for Chemistry , University of Groningen , Nijenborgh 4 , 9747 AG Groningen , The Netherlands.,Department of Radiology , University of Groningen, University Medical Center Groningen , Hanzeplein 1 , 9713 GZ Groningen , The Netherlands
| | - Ben L Feringa
- Center for Systems Chemistry, Stratingh Institute for Chemistry , University of Groningen , Nijenborgh 4 , 9747 AG Groningen , The Netherlands
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