1,151 results on '"1605 Organic Chemistry"'
Search Results
2. Identification of a BAZ2A-Bromodomain Hit Compound by Fragment Growing
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Andrea Dalle Vedove, Giulia Cazzanelli, Laurent Batiste, Jean-Rémy Marchand, Dimitrios Spiliotopoulos, Jessica Corsi, Vito Giuseppe D’Agostino, Amedeo Caflisch, Graziano Lolli, University of Zurich, Caflisch, Amedeo, and Lolli, Graziano
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BAZ2A bromodomain ,1303 Biochemistry ,Prostate cancer ,3002 Drug Discovery ,BAZ2A bromodomain, Prostate cancer, Fragment growing, X-ray crystallography, Molecular docking, Binding assays ,Organic Chemistry ,610 Medicine & health ,Fragment growing ,Biochemistry ,Molecular docking ,Drug Discovery ,10019 Department of Biochemistry ,570 Life sciences ,biology ,Binding assays ,1605 Organic Chemistry ,X-ray crystallography - Abstract
BAZ2A is an epigenetic regulator affecting transcription of ribosomal RNA. It is overexpressed in aggressive and recurrent prostate cancer, promoting cellular migration. Its bromodomain is characterized by a shallow and difficult-to-drug pocket. Here, we describe a structure-based fragment-growing campaign for the identification of ligands of the BAZ2A bromodomain. By combining docking, competition binding assays, and protein crystallography, we have extensively explored the interactions of the ligands with the rim of the binding pocket, and in particular ionic interactions with the side chain of Glu1820, which is unique to BAZ2A. We present 23 high-resolution crystal structures of the holo BAZ2A bromodomain and analyze common bromodomain/ligand motifs and favorable intraligand interactions. Binding of some of the compounds is enantiospecific, with affinity in the low micromolar range. The most potent ligand has an equilibrium dissociation constant of 7 μM and a good selectivity over the paralog BAZ2B bromodomain.
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- 2022
3. Organometallic Derivatives of Decoquinate Targeted toward Toxoplasma gondii
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Betts, Harley D, Ong, Yih Ching, Anghel, Nicoleta, Keller, Sarah, Karges, Johannes, Voutsara, Niovi, Müller, Joachim, Manoury, Eric, Blacque, Olivier, Cariou, Kevin, Hemphill, Andrew, Gasser, Gilles, Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL), Laboratoire de chimie de coordination (LCC), Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), ERC grant, European Project: 681679, H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC),681679,PhotoMedMet(2017), University of Zurich, Hemphill, Andrew, and Gasser, Gilles
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10120 Department of Chemistry ,1604 Inorganic Chemistry ,Organic Chemistry ,Toxoplasma gondii ,[CHIM.THER]Chemical Sciences/Medicinal Chemistry ,Inorganic Chemistry ,Medicinal Organometallic Chemistry ,Bioorganometallic Chemistry ,540 Chemistry ,Ferrocene ,Physical and Theoretical Chemistry ,1606 Physical and Theoretical Chemistry ,Toxoplasmosis ,1605 Organic Chemistry - Abstract
International audience; Toxoplasmosis is an infection contracted by exposure to Toxoplasma gondii and can have deleterious health effects on pregnant women and their children. Current treatments for the infection are complex and have considerable undesired side effects, raising the need for new treatments. Herein, we report the synthesis, characterization, and biological testing of some organometallic derivatives of the commercially available, broad-spectrum antiparasitic, decoquinate (DCQ). The cyclic secondary amine of decoquinate was functionalized with a range of groups (i.e., ferrocene, ruthenocene, and phenyl) with either methyl or vinyl bridges. Through measurement of half maximal inhibitory concentrations (IC50) and T. gondii proliferation assays, it was found that ferrocenylvinyl-DCQ and an oxygen-alkylated phenylvinyl-DCQ side product reduced proliferation of the parasite by 84% at 1 μM, which approached that of the parent drug (96%). These data provide a possible roadmap for future investigations on the derivatization of DCQ to yield better treatments for toxoplasmosis, particularly the functionalization of the cyclic ketone.
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- 2022
4. Allylic Carbocyclic Inhibitors Covalently Bind Glycoside Hydrolases
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Grayfer, Tatyana D, Yamani, Khalil, Jung, Erik, Chesnokov, Gleb A, Ferrara, Isabella, Hsiao, Chien-Chi, Georgiou, Antri, Michel, Jeremy, Bailly, Aurélien, Sieber, Simon, Eberl, Leo, Gademann, Karl, University of Zurich, and Gademann, Karl
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10120 Department of Chemistry ,1602 Analytical Chemistry ,10126 Department of Plant and Microbial Biology ,1601 Chemistry (miscellaneous) ,540 Chemistry ,580 Plants (Botany) ,10211 Zurich-Basel Plant Science Center ,1606 Physical and Theoretical Chemistry ,1605 Organic Chemistry - Published
- 2023
5. Transcriptional Response in Human Jurkat T Lymphocytes to a near Physiological Hypergravity Environment and to One Common in Routine Cell Culture Protocols
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Christian Vahlensieck, Cora Sandra Thiel, Meret Mosimann, Timothy Bradley, Fabienne Caldana, Jennifer Polzer, Beatrice Astrid Lauber, Oliver Ullrich, University of Zurich, Thiel, Cora Sandra, and Ullrich, Oliver
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10017 Institute of Anatomy ,1503 Catalysis ,1604 Inorganic Chemistry ,Organic Chemistry ,1607 Spectroscopy ,610 Medicine & health ,General Medicine ,Catalysis ,Computer Science Applications ,Inorganic Chemistry ,1312 Molecular Biology ,1706 Computer Science Applications ,570 Life sciences ,biology ,hypergravity ,transcriptomics ,mechanotransduction ,lymphocytes ,centrifugation ,Physical and Theoretical Chemistry ,1606 Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy ,1605 Organic Chemistry - Abstract
Cellular effects of hypergravity have been described in many studies. We investigated the transcriptional dynamics in Jurkat T cells between 20 s and 60 min of 9 g hypergravity and characterized a highly dynamic biphasic time course of gene expression response with a transition point between rapid adaptation and long-term response at approximately 7 min. Upregulated genes were shifted towards the center of the nuclei, whereby downregulated genes were shifted towards the periphery. Upregulated gene expression was mostly located on chromosomes 16–22. Protein-coding transcripts formed the majority with more than 90% of all differentially expressed genes and followed a continuous trend of downregulation, whereas retained introns demonstrated a biphasic time-course. The gene expression pattern of hypergravity response was not comparable with other stress factors such as oxidative stress, heat shock or inflammation. Furthermore, we tested a routine centrifugation protocol that is widely used to harvest cells for subsequent RNA analysis and detected a huge impact on the transcriptome compared to non-centrifuged samples, which did not return to baseline within 15 min. Thus, we recommend carefully studying the response of any cell types used for any experiments regarding the hypergravity time and levels applied during cell culture procedures and analysis.
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- 2023
6. Nutrition and Aging
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Mohajeri, M Hasan, University of Zurich, and Mohajeri, M Hasan
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10017 Institute of Anatomy ,1503 Catalysis ,1604 Inorganic Chemistry ,1312 Molecular Biology ,1706 Computer Science Applications ,570 Life sciences ,biology ,1607 Spectroscopy ,610 Medicine & health ,1606 Physical and Theoretical Chemistry ,1605 Organic Chemistry - Published
- 2023
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7. Effects of a Volatile Organic Compound Filter on Breath Profiles Measured by Secondary Electrospray High-Resolution Mass Spectrometry
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Ronja Weber, Jérôme Kaeslin, Sophia Moeller, Nathan Perkins, Srdjan Micic, Alexander Moeller, University of Zurich, Micic, Srdjan, and Moeller, Alexander
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1602 Analytical Chemistry ,Filter ,1601 Chemistry (miscellaneous) ,3002 Drug Discovery ,Organic Chemistry ,3003 Pharmaceutical Science ,Pharmaceutical Science ,610 Medicine & health ,SESI-HRMS ,Ambient air ,Analytical Chemistry ,filter ,volatile organic compounds ,contaminants ,metabolites ,ambient air ,Chemistry (miscellaneous) ,10036 Medical Clinic ,Contaminants ,1313 Molecular Medicine ,Drug Discovery ,Metabolites ,Molecular Medicine ,Volatile organic compounds ,Physical and Theoretical Chemistry ,1606 Physical and Theoretical Chemistry ,1605 Organic Chemistry - Abstract
Environmental volatile organic compounds (VOCs) from the ambient air potentially influence on-line breath analysis measurements by secondary electrospray ionization high-resolution mass spectrometry (SESI-HRMS). The aim of this study was to investigate how inhaling through a VOC filter affects the detected breath profiles and whether it is feasible to integrate such filters into routine measurements. A total of 24 adult participants performed paired breath analysis measurements with and without the use of an activated carbon filter for inspiration. Concordance correlation coefficients (CCCs) and the Bland–Altman analysis were used to assess the agreement between the two methods. Additionally, the effect on a selection of known metabolites and contaminants was analyzed. Out of all the detected features, 78.3% showed at least a moderate agreement before and after filter usage (CCC > 0.9). The decrease in agreement of the remaining m/z features was mostly associated with reduced signal intensities after filter usage. Although a moderate-to-substantial concordance was found for almost 80% of the m/z features, the filter still had an effect by decreasing signal intensities, not only for contaminants, but also for some of the studied metabolites. Operationally, the use of the filter complicated and slowed down the conductance of measurements, limiting its applicability in clinical studies., Molecules, 28 (1), ISSN:1420-3049
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- 2022
8. ChemR23 signaling ameliorates cognitive impairments in diabetic mice via dampening oxidative stress and NLRP3 inflammasome activation
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Jiawei Zhang, Lan Liu, Yaxuan Zhang, Yuan Yuan, Zhijuan Miao, Kaili Lu, Xiaojie Zhang, Ruiqing Ni, Haibing Zhang, Yuwu Zhao, Xiuzhe Wang, University of Zurich, Zhao, Yuwu, and Wang, Xiuzhe
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Inflammasomes ,Organic Chemistry ,Clinical Biochemistry ,610 Medicine & health ,11359 Institute for Regenerative Medicine (IREM) ,1308 Clinical Biochemistry ,Biochemistry ,NLRP3 inflammasome ,Diabetes Mellitus, Experimental ,ChemR23 ,Mice ,Oxidative Stress ,Diabetes mellitus ,Cognitive impairment ,NLR Family, Pyrin Domain-Containing 3 Protein ,Animals ,Cognitive Dysfunction ,Oxidative stress ,1605 Organic Chemistry - Abstract
Diabetes mellitus is associated with cognitive impairment characterized by memory loss and cognitive inflexibility. Recent studies have revealed that ChemR23 is implicated in both diabetes mellitus and Alzheimer's disease. However, the impact of ChemR23 on diabetes-associated cognitive impairment remains elusive. In this study, we explored the longitudinal changes of ChemR23 expression and cognitive function in STZ-induced type 1 diabetic mice and leptin receptor knockout type 2 diabetic mice at different ages. We also treated diabetic mice with ChemR23 agonists RvE1 or chemerin-9 to explore whether ChemR23 activation could alleviate diabetes-associated cognitive impairment. The underlying mechanism was further investigated in diabetic mice with genetic deletion of ChemR23. The results showed that ChemR23 expression was decreased along with aging and the progression of diabetes, suggesting that abnormal ChemR23 signaling may be involved in diabetes-associated cognitive impairment. Administration of RvE1 or chemerin-9 ameliorated oxidative stress and inhibited NLRP3 inflammasome activation through Nrf2/TXNIP pathway, and ultimately alleviated cognitive impairment in diabetic mice. Depletion of ChemR23 in diabetic mice abolished the beneficial effects of RvE1 and chemerin-9, and exacerbated cognitive impairment via increasing oxidative stress and activating NLRP3 inflammasome. Collectively, our data highlight the crucial role of ChemR23 signaling in diabetes-associated cognitive impairment via regulating oxidative stress and NLRP3 inflammasome, and targeting ChemR23 may serve as a promising novel strategy for the treatment of diabetes-associated cognitive impairment., Redox Biology, 58, ISSN:2213-2317
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- 2022
9. Hemoglobin is an oxygen-dependent glutathione buffer adapting the intracellular reduced glutathione levels to oxygen availability
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Simone Fenk, Elizaveta V. Melnikova, Anastasia A. Anashkina, Yuri M. Poluektov, Pavel I. Zaripov, Vladimir A. Mitkevich, Yaroslav V. Tkachev, Lars Kaestner, Giampaolo Minetti, Heimo Mairbäurl, Jeroen S. Goede, Alexander A. Makarov, Irina Yu Petrushanko, Anna Bogdanova, University of Zurich, and Bogdanova, Anna
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Erythrocytes ,Organic Chemistry ,Clinical Biochemistry ,1308 Clinical Biochemistry ,10081 Institute of Veterinary Physiology ,Glutathione ,Biochemistry ,Oxygen ,Hemoglobins ,Oxyhemoglobins ,10076 Center for Integrative Human Physiology ,Humans ,570 Life sciences ,biology ,11434 Center for Clinical Studies ,1605 Organic Chemistry - Abstract
Fast changes in environmental oxygen availability translate into shifts in mitochondrial free radical production. An increase in intraerythrocytic reduced glutathione (GSH) during deoxygenation would support the detoxification of exogenous oxidants released into the circulation from hypoxic peripheral tissues. Although reported, the mechanism behind this acute oxygen-dependent regulation of GSH in red blood cells remains unknown. This study explores the role of hemoglobin (Hb) in the oxygen-dependent modulation of GSH levels in red blood cells. We have demonstrated that a decrease in Hb O
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- 2022
10. X-ray Structures and Computational Studies of Two Bioactive 2-(Adamantane-1-carbonyl)-N-substituted Hydrazine-1-carbothioamides
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Al-Wahaibi, Lamya H, Alagappan, Kowsalya, Blacque, Olivier, Mohamed, Ahmed A B, Hassan, Hanan M, Percino, María Judith, El-Emam, Ali A, Thamotharan, Subbiah, University of Zurich, El-Emam, Ali A, and Thamotharan, Subbiah
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10120 Department of Chemistry ,1602 Analytical Chemistry ,1601 Chemistry (miscellaneous) ,3002 Drug Discovery ,Organic Chemistry ,3003 Pharmaceutical Science ,Pharmaceutical Science ,Analytical Chemistry ,Chemistry (miscellaneous) ,1313 Molecular Medicine ,540 Chemistry ,Drug Discovery ,adamantane ,hydrazine-1-carbothioamide ,Hirshfeld surface ,CLP–Pixel ,QTAIM ,molecular docking ,urease inhibition ,antiproliferative agents ,H-H bonding ,Molecular Medicine ,Physical and Theoretical Chemistry ,1606 Physical and Theoretical Chemistry ,1605 Organic Chemistry - Abstract
Two biologically active adamantane-linked hydrazine-1-carbothioamide derivatives, namely 2-(adamantane-1-carbonyl)-N-(tert-butyl)hydrazine-1-carbothioamide) 1 and 2-(adamantane-1-carbonyl)-N-cyclohexylhydrazine-1-carbothioamide 2, have been synthesized. X-ray analysis was conducted to study the effect of the t-butyl and cyclohexyl moieties on the intermolecular interactions and conformation of the molecules in the solid state. X-ray analysis reveals that compound 1 exhibits folded conformation, whereas compound 2 adopts extended conformation. The Hirshfeld surface analysis indicates that the contributions of the major intercontacts involved in the stabilization of the crystal structures do not change much as a result of the t-butyl and cyclohexyl moieties. However, the presence and absence of these contacts is revealed by the 2D-fingerprint plots. The CLP–Pixel method was used to identify the energetically significant molecular dimers. These dimers are stabilized by different types of intermolecular interactions such as N–H···S, N–H···O, C–H···S, C–H···O, H–H bonding and C–H···π interactions. The strength of these interactions was quantified by using the QTAIM approach. The results suggest that N–H···O interaction is found to be stronger among other interactions. The in vitro assay suggests that both compounds 1 and 2 exhibit urease inhibition potential, and these compounds also display moderate antiproliferative activities. Molecular docking analysis shows the key interaction between urease enzyme and title compounds.
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- 2022
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11. Conglomerate Aggregation of 7,12,17-Trioxa[11]helicene into Homochiral Two-Dimensional Crystals on the Cu(100) Surface
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Bahaaeddin Irziqat, Jan Berger, Aleksandra Cebrat, Jesús I. Mendieta‐Moreno, Mothuku Shyam Sundar, Ashutosh V. Bedekar, Karl‐Heinz Ernst, University of Zurich, and Ernst, Karl‐Heinz
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10120 Department of Chemistry ,1303 Biochemistry ,1503 Catalysis ,1604 Inorganic Chemistry ,3002 Drug Discovery ,Organic Chemistry ,Biochemistry ,Catalysis ,Inorganic Chemistry ,540 Chemistry ,Drug Discovery ,Physical and Theoretical Chemistry ,1606 Physical and Theoretical Chemistry ,1605 Organic Chemistry - Published
- 2022
12. The Farnesoid X Receptor as a Master Regulator of Hepatotoxicity
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Magdalena Rausch, Sophia L. Samodelov, Michele Visentin, Gerd A. Kullak-Ublick, University of Zurich, and Visentin, Michele
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1503 Catalysis ,1604 Inorganic Chemistry ,Organic Chemistry ,Receptors, Cytoplasmic and Nuclear ,1607 Spectroscopy ,610 Medicine & health ,General Medicine ,Lipids ,Catalysis ,Computer Science Applications ,Bile Acids and Salts ,Inorganic Chemistry ,10199 Clinic for Clinical Pharmacology and Toxicology ,1312 Molecular Biology ,1706 Computer Science Applications ,Humans ,Homeostasis ,Chemical and Drug Induced Liver Injury ,Physical and Theoretical Chemistry ,1606 Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy ,1605 Organic Chemistry - Abstract
The nuclear receptor farnesoid X receptor (FXR, NR1H4) is a bile acid (BA) sensor that links the enterohepatic circuit that regulates BA metabolism and elimination to systemic lipid homeostasis. Furthermore, FXR represents a real guardian of the hepatic function, preserving, in a multifactorial fashion, the integrity and function of hepatocytes from chronic and acute insults. This review summarizes how FXR modulates the expression of pathway-specific as well as polyspecific transporters and enzymes, thereby acting at the interface of BA, lipid and drug metabolism, and influencing the onset and progression of hepatotoxicity of varying etiopathogeneses. Furthermore, this review article provides an overview of the advances and the clinical development of FXR agonists in the treatment of liver diseases.
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- 2022
13. An Extremely Stable Interprotein Tetrahedral Hg(Cys) 4 Core Forms in the Zinc Hook Domain of Rad50 Protein at Physiological pH
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Marek Łuczkowski, Michał Padjasek, Józef Ba Tran, Lars Hemmingsen, Olga Kerber, Jelena Habjanič, Eva Freisinger, Artur Krężel, University of Zurich, and Krężel, Artur
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10120 Department of Chemistry ,Cys-rich protein ,COORDINATION ,STABILITY ,1503 Catalysis ,HG-199 NMR ,Organic Chemistry ,DNA-REPLICATION ,METAL-BINDING PROPERTIES ,MRE11-RAD50-NBS1 COMPLEX ,General Chemistry ,stability constant ,metal-sulfur cluster ,MERCURY(II) COMPLEXES ,MERCURIC-CHLORIDE ,Catalysis ,STRAND BREAK REPAIR ,540 Chemistry ,affinity ,FORMATION-CONSTANTS ,mercury toxicity ,1605 Organic Chemistry - Abstract
In nature, thiolate-based systems are the primary targets of divalent mercury (Hg-II) toxicity. The formation of Hg(Cys)(x) cores in catalytic and structural protein centers mediates mercury's toxic effects and ultimately leads to cellular damage. Multiple studies have revealed distinct Hg-II-thiolate coordination preferences, among which linear Hg-II complexes are the most commonly observed in solution at physiological pH. Trigonal or tetrahedral geometries are formed at basic pH or in tight intraprotein Cys-rich metal sites. So far, no interprotein tetrahedral Hg-II complex formed at neutral pH has been reported. Rad50 protein is a part of the multiprotein MRN complex, a major player in DNA damage-repair processes. Its central region consists of a conserved CXXC motif that enables dimerization of two Rad50 molecules by coordinating Zn-II. Dimerized motifs form a unique interprotein zinc hook domain (Hk) that is critical for the biological activity of the MRN. Using a series of length-differentiated peptide models of the Pyrococcus furiosus zinc hook domain, we investigated its interaction with Hg-II. Using UV-Vis, CD, PAC, and Hg-199 NMR spectroscopies as well as anisotropy decay, we discovered that all Rad50 fragments preferentially form homodimeric Hg(Hk)(2) species with a distorted tetrahedral HgS4 coordination environment at physiological pH; this is the first example of an interprotein mercury site displaying tetrahedral geometry in solution. At higher Hg-II content, monomeric HgHk complexes with linear geometry are formed. The Hg(Cys)(4) core of Rad50 is extremely stable and does not compete with cyanides, NAC, or DTT. Applying ITC, we found that the stability constant of the Rad50 Hg(Hk)(2) complex is approximately three orders of magnitude higher than those of the strongest Hg-II complexes known to date.
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- 2022
14. Gene Therapy in Combination with Nitrogen Scavenger Pretreatment Corrects Biochemical and Behavioral Abnormalities of Infant Citrullinemia Type 1 Mice
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Andrea Bazo, Aquilino Lantero, Itsaso Mauleón, Leire Neri, Martin Poms, Johannes Häberle, Ana Ricobaraza, Bernard Bénichou, Jean-Philippe Combal, Gloria Gonzalez-Aseguinolaza, Rafael Aldabe, University of Zurich, and Aldabe, Rafael
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1503 Catalysis ,1604 Inorganic Chemistry ,gene therapy ,rAAV ,urea cycle ,hyperammonemia ,citrullinemia ,Organic Chemistry ,1607 Spectroscopy ,610 Medicine & health ,General Medicine ,Catalysis ,Computer Science Applications ,Inorganic Chemistry ,10036 Medical Clinic ,1312 Molecular Biology ,1706 Computer Science Applications ,Physical and Theoretical Chemistry ,1606 Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy ,1605 Organic Chemistry - Abstract
Citrullinemia type I (CTLN1) is a rare autosomal recessive disorder caused by mutations in the gene encoding argininosuccinate synthetase 1 (ASS1) that catalyzes the third step of the urea cycle. CTLN1 patients suffer from impaired elimination of nitrogen, which leads to neurotoxic levels of circulating ammonia and urea cycle byproducts that may cause severe metabolic encephalopathy, death or irreversible brain damage. Standard of care (SOC) of CTLN1 consists of daily nitrogen-scavenger administration, but patients remain at risk of life-threatening decompensations. We evaluated the therapeutic efficacy of a recombinant adeno-associated viral vector carrying the ASS1 gene under the control of a liver-specific promoter (VTX-804). When administered to three-week-old CTLN1 mice, all the animals receiving VTX-804 in combination with SOC gained body weight normally, presented with a normalization of ammonia and reduction of citrulline levels in circulation, and 100% survived for 7 months. Similar to what has been observed in CTLN1 patients, CTLN1 mice showed several behavioral abnormalities such as anxiety, reduced welfare and impairment of innate behavior. Importantly, all clinical alterations were notably improved after treatment with VTX-804. This study demonstrates the potential of VTX-804 gene therapy for future clinical translation to CTLN1 patients.
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- 2022
15. Severe Obstructive Sleep Apnea Disrupts Vigilance-State-Dependent Metabolism
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Schmidt, Felix, Nowak, Nora, Baumgartner, Patrick, Gaisl, Thomas, Malesevic, Stefan, Streckenbach, Bettina, Sievi, Noriane A, Schwarz, Esther I, Zenobi, Renato, Brown, Steven A, Kohler, Malcolm, University of Zurich, and Kohler, Malcolm
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1503 Catalysis ,1607 Spectroscopy ,610 Medicine & health ,Disorders of Excessive Somnolence ,obstructive sleep apnea ,sleep ,metabolomics ,breath analysis ,secondary electrospray ionization ,mitochondria ,Catalysis ,Inorganic Chemistry ,1312 Molecular Biology ,1706 Computer Science Applications ,Humans ,Wakefulness ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy ,Sleep Apnea, Obstructive ,1604 Inorganic Chemistry ,Organic Chemistry ,General Medicine ,Computer Science Applications ,Oxygen ,10178 Clinic for Pneumology ,1606 Physical and Theoretical Chemistry ,1605 Organic Chemistry - Abstract
The direct pathophysiological effects of obstructive sleep apnea (OSA) have been well described. However, the systemic and metabolic consequences of OSA are less well understood. The aim of this secondary analysis was to translate recent findings in healthy subjects on vigilance-state-dependent metabolism into the context of OSA patients and answer the question of how symptomatic OSA influences metabolism and whether these changes might explain metabolic and cardiovascular consequences of OSA. Patients with suspected OSA were assigned according to their oxygen desaturation index (ODI) and Epworth Sleepiness Scale (ESS) score into symptomatic OSA and controls. Vigilance-state-dependent breath metabolites assessed by high-resolution mass spectrometry were used to test for a difference in both groups. In total, 44 patients were eligible, of whom 18 (40.9%) were assigned to the symptomatic OSA group. Symptomatic OSA patients with a median [25%, 75% quartiles] ODI of 40.5 [35.0, 58.8] events/h and an ESS of 14.0 [11.2, 15.8] showed moderate to strong evidence for differences in 18 vigilance-state-dependent breath compounds compared to controls. These identified metabolites are part of major metabolic pathways in carbohydrate, amino acid, and lipid metabolism. Thus, beyond hypoxia per se, we hypothesize that disturbed sleep in OSA patients persists as disturbed sleep-dependent metabolite levels during daytime., International Journal of Molecular Sciences, 23 (22), ISSN:1422-0067
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- 2022
16. Weak Noncovalent Interactions in Three Closely Related Adamantane-Linked 1,2,4-Triazole N-Mannich Bases: Insights from Energy Frameworks, Hirshfeld Surface Analysis, In Silico 11β-HSD1 Molecular Docking and ADMET Prediction
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Lamya H. Al-Wahaibi, Mario A. Macías, Olivier Blacque, Luke S. Zondagh, Jacques Joubert, Subbiah Thamotharan, María Judith Percino, Ahmed A. B. Mohamed, Ali A. El-Emam, University of Zurich, Al-Wahaibi, Lamya H, and El-Emam, Ali A
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10120 Department of Chemistry ,1602 Analytical Chemistry ,1601 Chemistry (miscellaneous) ,3002 Drug Discovery ,Organic Chemistry ,3003 Pharmaceutical Science ,Pharmaceutical Science ,Analytical Chemistry ,adamantane ,1,2,4-triazole ,single crystal X-ray ,Hirshfeld surface analysis ,molecular docking ,ADMET prediction ,11β-HSD1 inhibitors ,Chemistry (miscellaneous) ,1313 Molecular Medicine ,540 Chemistry ,Drug Discovery ,Molecular Medicine ,Physical and Theoretical Chemistry ,1606 Physical and Theoretical Chemistry ,1605 Organic Chemistry - Abstract
Structural analysis and docking studies of three adamantane-linked 1,2,4-triazole N-Mannich bases (1–3) are presented. Compounds 1, 2 and 3 crystallized in the monoclinic P21/c, P21 and P21/n space groups, respectively. Crystal packing of 1 was stabilized by intermolecular C-H⋯O interactions, whereas compounds 2 and 3 were stabilized through intermolecular C-H⋯N, C-H⋯S and C-H⋯π interactions. The energy frameworks for crystal structures of 1–3 were described. The substituent effect on the intermolecular interactions and their contributions were described on the basis of Hirshfeld surface analyses. The 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibition potential, pharmacokinetic and toxicity profiles of compounds 1–3 were determined using in silico techniques. Molecular docking of the compounds into the 11β-HSD1 active site showed comparable binding affinity scores (−7.50 to −8.92 kcal/mol) to the 11β-HSD1 co-crystallized ligand 4YQ (−8.48 kcal/mol, 11β-HSD1 IC50 = 9.9 nM). The compounds interacted with key active site residues, namely Ser170 and Tyr183, via strong hydrogen bond interactions. The predicted pharmacokinetic and toxicity profiles of the compounds were assessed, and were found to exhibit excellent ADMET potential.
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- 2022
17. Cross-Coupling Reactions of 5-Bromo-1,2,3-triazine
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Hoff, Lukas V, Hauser, Joana M, Gademann, Karl, University of Zurich, and Gademann, Karl
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10120 Department of Chemistry ,Pyrimidines ,Triazines ,Pyridines ,540 Chemistry ,Organic Chemistry ,Boronic Acids ,Catalysis ,1605 Organic Chemistry - Abstract
An efficient Pd catalyzed cross-coupling method for 5-bromo-1,2,3-triazine is described. Optimization of the reaction conditions allowed for the preparation of a representative scope of (hetero)aryl-1,2,3-triazines (20 examples, up to 97% yield). The reaction scope was evaluated using a data science enabled boronic acid chemical space to assess the generality of the method. Additionally, diversification of the resulting products enabled the preparation of pyrimidines and pyridines in yields of up to 80% and in only two steps.
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- 2022
18. Analyses of circRNA Expression throughout the Light-Dark Cycle Reveal a Strong Regulation of Cdr1as, Associated with Light Entrainment in the SCN
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Andranik Ivanov, Daniele Mattei, Kathrin Radscheit, Anne-Claire Compagnion, Jan Patrick Pett, Hanspeter Herzel, Rosa Chiara Paolicelli, Monika Piwecka, Urs Meyer, Dieter Beule, University of Zurich, and Ivanov, Andranik
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1503 Catalysis ,1604 Inorganic Chemistry ,Organic Chemistry ,1607 Spectroscopy ,10079 Institute of Veterinary Pharmacology and Toxicology ,General Medicine ,Catalysis ,Computer Science Applications ,Inorganic Chemistry ,Cardiovascular and Metabolic Diseases ,1312 Molecular Biology ,1706 Computer Science Applications ,570 Life sciences ,biology ,Technology Platforms ,Physical and Theoretical Chemistry ,1606 Physical and Theoretical Chemistry ,Molecular Biology ,circular RNA (circRNA) ,Cdr1as ,circadian rhythm ,suprachiasmatic nucleus ,SCN ,non-coding RNA ,Cyrano ,light entrainment ,miR-7 ,light-dark ,wake-sleep ,Spectroscopy ,1605 Organic Chemistry - Abstract
Circular RNAs (circRNAs) are a large class of relatively stable RNA molecules that are highly expressed in animal brains. Many circRNAs have been associated with CNS disorders accompanied by an aberrant wake-sleep cycle. However, the regulation of circRNAs in brain homeostasis over daily light-dark (LD) cycles has not been characterized. Here, we aim to quantify the daily expression changes of circRNAs in physiological conditions in healthy adult animals. Using newly generated and public RNA-Seq data, we monitored circRNA expression throughout the 12:12 h LD cycle in various mouse brain regions. We identified that Cdr1as, a conserved circRNA that regulates synaptic transmission, is highly expressed in the suprachiasmatic nucleus (SCN), the master circadian pacemaker. Despite its high stability, Cdr1as has a very dynamic expression in the SCN throughout the LD cycle, as well as a significant regulation in the hippocampus following the entry into the dark phase. Computational integration of different public datasets predicted that Cdr1as is important for regulating light entrainment in the SCN. We hypothesize that the expression changes of Cdr1as in the SCN, particularly during the dark phase, are associated with light-induced phase shifts. Importantly, our work revises the current beliefs about natural circRNA stability and suggests that the time component must be considered when studying circRNA regulation.
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- 2022
19. NLRP1 in Cutaneous SCCs: An Example of the Complex Roles of Inflammasomes in Cancer Development
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Di Filippo, Michela, Hennig, Paulina, Karakaya, Tugay, Slaufova, Marta, Beer, Hans-Dietmar, University of Zurich, and Beer, Hans-Dietmar
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1503 Catalysis ,1604 Inorganic Chemistry ,Organic Chemistry ,10177 Dermatology Clinic ,1607 Spectroscopy ,610 Medicine & health ,General Medicine ,Catalysis ,Computer Science Applications ,Inorganic Chemistry ,1312 Molecular Biology ,1706 Computer Science Applications ,Physical and Theoretical Chemistry ,1606 Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy ,1605 Organic Chemistry - Published
- 2022
20. Enzymatic Construction of DARPin-Based Targeted Delivery Systems Using Protein Farnesyltransferase and a Capture and Release Strategy
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Yi Zhang, Yiao Wang, Safak Uslu, Sneha Venkatachalapathy, Mohammad Rashidian, Jonas V. Schaefer, Andreas Plückthun, Mark D. Distefano, University of Zurich, and Distefano, Mark D
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1503 Catalysis ,1607 Spectroscopy ,610 Medicine & health ,Catalysis ,Inorganic Chemistry ,Escherichia coli ,10019 Department of Biochemistry ,1312 Molecular Biology ,1706 Computer Science Applications ,Humans ,Designed Ankyrin Repeat Proteins ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy ,Aldehydes ,Alkyl and Aryl Transferases ,1604 Inorganic Chemistry ,Organic Chemistry ,protein farnesyltransferase ,site-specific protein conjugation ,biorthogonal conjugation ,targeted drug delivery ,Proteins ,General Medicine ,Epithelial Cell Adhesion Molecule ,Ankyrin Repeat ,Computer Science Applications ,570 Life sciences ,biology ,1606 Physical and Theoretical Chemistry ,1605 Organic Chemistry - Abstract
Protein-based conjugates have been extensively utilized in various biotechnological and therapeutic applications. In order to prepare homogeneous conjugates, site-specific modification methods and efficient purification strategies are both critical factors to be considered. The development of general and facile conjugation and purification strategies is therefore highly desirable. Here, we apply a capture and release strategy to create protein conjugates based on Designed Ankyrin Repeat Proteins (DARPins), which are engineered antigen-binding proteins with prominent affinity and selectivity. In this case, DARPins that target the epithelial cell adhesion molecule (EpCAM), a diagnostic cell surface marker for many types of cancer, were employed. The DARPins were first genetically modified with a C-terminal CVIA sequence to install an enzyme recognition site and then labeled with an aldehyde functional group employing protein farnesyltransferase. Using a capture and release strategy, conjugation of the labeled DARPins to a TAMRA fluorophore was achieved with either purified proteins or directly from crude E. coli lysate and used in subsequent flow cytometry and confocal imaging analysis. DARPin-MMAE conjugates were also prepared yielding a construct manifesting an IC50 of 1.3 nM for cell killing of EpCAM positive MCF-7 cells. The method described here is broadly applicable to enable the streamlined one-step preparation of protein-based conjugates.
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- 2022
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21. High-Yield 99mTc Labeling of Gold Nanoparticles Carrying Atropine and Adrenaline
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Mattern, Annabelle, Habermann, Sebastian, Zegke, Markus, Wickleder, Mathias Siegfried, Alberto, Roger, University of Zurich, and Alberto, Roger
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10120 Department of Chemistry ,Pharmacology ,1502 Bioengineering ,Organic Chemistry ,3003 Pharmaceutical Science ,Biomedical Engineering ,2204 Biomedical Engineering ,Pharmaceutical Science ,Bioengineering ,3004 Pharmacology ,540 Chemistry ,1305 Biotechnology ,1605 Organic Chemistry ,Biotechnology - Published
- 2022
22. Fragment Ligands of the m$^{6}$A-RNA Reader YTHDF2
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Nai, Francesco, Nachawati, Raed, Zálešák, František, Wang, Xiang, Li, Yaozong, Caflisch, Amedeo, University of Zurich, Li, Yaozong, and Caflisch, Amedeo
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1303 Biochemistry ,3002 Drug Discovery ,10019 Department of Biochemistry ,570 Life sciences ,biology ,610 Medicine & health ,1605 Organic Chemistry - Published
- 2022
23. Boron Trifluoride-Mediated Cycloaddition of 3-Bromotetrazine and Silyl Enol Ethers: Synthesis of 3-Bromo-pyridazines
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Jan Sklyaruk, Karl Gademann, Simon D. Schnell, Anthony Linden, Jorge A. González, University of Zurich, and Gademann, Karl
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10120 Department of Chemistry ,Cycloaddition Reaction ,Silylation ,Chemistry ,Organic Chemistry ,Regioselectivity ,Combinatorial chemistry ,Enol ,Cycloaddition ,Pyridazines ,chemistry.chemical_compound ,Alcohols ,540 Chemistry ,Boranes ,Boron trifluoride ,1605 Organic Chemistry ,Ethers - Abstract
Pyridazines are important scaffolds for medicinal chemistry or crop protection agents, yet the selective preparation of 3-bromo-pyridazines with high regiocontrol remains difficult. We achieved the Lewis acid-mediated inverse electron demand Diels-Alder reaction between 3-monosubstituted s-tetrazine and silyl enol ethers and obtained functionalized pyridazines. In the case of 1-monosubstituted silyl enol ethers, exclusive regioselectivity was observed. Downstream functionalization of the resulting 3-bromo-pyridazines was demonstrated utilizing several cross-coupling protocols to synthesize 3,4-disubstituted pyridazines with excellent control over the substitution pattern.
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- 2021
24. Stereospecific on‐Surface Cyclodehydrogenation of Bishelicenes: Preservation of Handedness from Helical to Planar Chirality
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Irziqat, Bahaaeddin, Cebrat, Aleksandra, Baljozović, Miloš, Martin, Kévin, Parschau, Manfred, Avarvari, Narcis, Ernst, Karl‐Heinz, Ernst, Karl-Heinz, Scott, Lawrence, Kühnle, Angelika, Crassous, Jeanne, Bednarova, Lucie, De Feyter, Steven, University of Zurich, Ernst, Karl‐Heinz, MOLTECH-Anjou, Université d'Angers (UA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Swiss Federal Laboratories for Materials Science and Technology [Dübendorf] (EMPA)
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10120 Department of Chemistry ,Surface (mathematics) ,1503 Catalysis ,UFSP13-6 Solar Light to Chemical Energy Conversion ,chirality ,surface chemistry ,polyaromatic hydrocarbons Manuscript Classifications: Chirality ,Planar chirality ,010402 general chemistry ,01 natural sciences ,Catalysis ,law.invention ,helicenes ,Planar ,Stereospecificity ,law ,540 Chemistry ,[CHIM]Chemical Sciences ,Monolayers ,polyaromatic hydrocarbons ,010405 organic chemistry ,Chemistry ,Communication ,Organic Chemistry ,General Chemistry ,Communications ,0104 chemical sciences ,Crystallography ,Scanning probe microscopy ,scanning tunneling microscopy ,on-surface chemistry ,Scanning tunneling microscope ,Enantiomer ,Chirality (chemistry) ,1605 Organic Chemistry - Abstract
Flattening helices while keeping the handedness: On-surface cyclodehydrogenation of bishelicene enantiomers leads stereospecifically to (M,M) and (P,P) chiral planar polyaromatic hydrocarbons. This is followed by their homochiral aggregation into a 2D conglomerate. Thermally induced cyclodehydrogenation proceeds stereospecifically to chiral, planar coronocoronene. Such a reaction is a special example of topochemistry in which enantiospecific conversion is supported by the alignment of the reactant by the surface.
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- 2021
25. METTL3 Inhibitors for Epitranscriptomic Modulation of Cellular Processes
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A. Dolbois, Elena Bochenkova, Amedeo Caflisch, Elena V. Moroz-Omori, Maciej D. Rzeczkowski, L. Wiedmer, Paweł Śledź, Sherry J. Cheriyamkunnel, R.K. Bedi, Danzhi Huang, University of Zurich, Moroz-Omori, Elena V, and Caflisch, Amedeo
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Cell cycle checkpoint ,1303 Biochemistry ,Methyltransferase ,RNA methyltransferase inhibitor ,Biochemistry ,chemistry.chemical_compound ,0302 clinical medicine ,Drug Discovery ,Enzyme Inhibitors ,RNA, Small Interfering ,General Pharmacology, Toxicology and Pharmaceutics ,chemistry.chemical_classification ,0303 health sciences ,Full Paper ,Molecular Structure ,3002 Drug Discovery ,leukemia ,Assay ,Methylation ,Full Papers ,3. Good health ,3004 Pharmacology ,030220 oncology & carcinogenesis ,Molecular Medicine ,Growth inhibition ,610 Medicine & health ,3000 General Pharmacology, Toxicology and Pharmaceutics ,Structure-Activity Relationship ,03 medical and health sciences ,Epitranscriptomics ,10019 Department of Biochemistry ,Humans ,Viability assay ,030304 developmental biology ,Pharmacology ,Messenger RNA ,Dose-Response Relationship, Drug ,Organic Chemistry ,RNA ,m6A ,Methyltransferases ,Molecular biology ,Enzyme ,chemistry ,Apoptosis ,Cell culture ,1313 Molecular Medicine ,METTL3 ,570 Life sciences ,biology ,epitranscriptomics ,Caco-2 Cells ,1605 Organic Chemistry - Abstract
The methylase METTL3 is the writer enzyme of the N6‐methyladenosine (m6A) modification of RNA. Using a structure‐based drug discovery approach, we identified a METTL3 inhibitor with potency in a biochemical assay of 280 nM, while its enantiomer is 100 times less active. We observed a dose‐dependent reduction in the m6A methylation level of mRNA in several cell lines treated with the inhibitor already after 16 h of treatment, which lasted for at least 6 days. Importantly, the prolonged incubation (up to 6 days) with the METTL3 inhibitor did not alter levels of other RNA modifications (i. e., m1A, m6Am, m7G), suggesting selectivity of the developed compound towards other RNA methyltransferases., Writer's block: We developed and characterized a small‐molecule inhibitor of m6A writer METTL3 by protein crystallography, biochemical and cellular assays. It shows high‐nanomolar potency in the biochemical assay, good selectivity against a panel of protein methyltransferases and kinases, and it reduced m6A/A ratio in mRNAs of different cell lines. In addition, we confirmed the selectivity of our compound towards other RNA methyltransferases in living cells.
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- 2021
26. Modular Adapters Utilizing Binders of Different Molecular Types Expand Cell-Targeting Options for Adenovirus Gene Delivery
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Freitag, Patrick C, Brandl, Fabian, Brücher, Dominik, Weiss, Fabian, Dreier, Birgit, Plückthun, Andreas, University of Zurich, and Plückthun, Andreas
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Pharmacology ,1502 Bioengineering ,Organic Chemistry ,Genetic Vectors ,3003 Pharmaceutical Science ,Biomedical Engineering ,2204 Biomedical Engineering ,Pharmaceutical Science ,610 Medicine & health ,Bioengineering ,Genetic Therapy ,Ligands ,Adenoviridae ,3004 Pharmacology ,10019 Department of Biochemistry ,1305 Biotechnology ,570 Life sciences ,biology ,Humans ,Receptors, Neurotensin ,Folate Receptor 1 ,1605 Organic Chemistry ,Biotechnology ,Single-Chain Antibodies - Abstract
Efficient and cell-specific delivery of DNA is essential for the effective and safe use of gene delivery technologies. Consequently, a large variety of technologies have been developed and applied in a wide range of
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- 2022
27. A preclinical study on brugada syndrome with a CACNB2 variant using human cardiomyocytes from induced pluripotent stem cells
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Rujia Zhong, Theresa Schimanski, Feng Zhang, Huan Lan, Alyssa Hohn, Qiang Xu, Mengying Huang, Zhenxing Liao, Lin Qiao, Zhen Yang, Yingrui Li, Zhihan Zhao, Xin Li, Lena Rose, Sebastian Albers, Lasse Maywald, Jonas Müller, Hendrik Dinkel, Ardan Saguner, Johannes W. G. Janssen, Narasimha Swamy, Yannick Xi, Siegfried Lang, Mandy Kleinsorge, Firat Duru, Xiaobo Zhou, Sebastian Diecke, Lukas Cyganek, Ibrahim Akin, Ibrahim El-Battrawy, University of Zurich, and Zhou, Xiaobo
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Calcium Channels, L-Type ,1503 Catalysis ,Induced Pluripotent Stem Cells ,Action Potentials ,1607 Spectroscopy ,610 Medicine & health ,Catalysis ,Inorganic Chemistry ,1312 Molecular Biology ,1706 Computer Science Applications ,Bisoprolol ,Humans ,Brugada syndrome ,arrhythmias ,human-induced pluripotent stem cell-derived cardiomyocytes ,CACNB gene ,Myocytes, Cardiac ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy ,Brugada Syndrome ,1604 Inorganic Chemistry ,Organic Chemistry ,Arrhythmias, Cardiac ,General Medicine ,Quinidine ,Computer Science Applications ,10209 Clinic for Cardiology ,Technology Platforms ,1606 Physical and Theoretical Chemistry ,1605 Organic Chemistry - Abstract
Aims: Some gene variants in the sodium channels, as well as calcium channels, have been associated with Brugada syndrome (BrS). However, the investigation of the human cellular phenotype and the use of drugs for BrS in presence of variant in the calcium channel subunit is still lacking. Objectives: The objective of this study was to establish a cellular model of BrS in the presence of a CACNB2 variant of uncertain significance (c.425C > T/p.S142F) using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and test drug effects using this model. Methods and results: This study recruited cells from a patient with Brugada syndrome (BrS) and recurrent ventricular fibrillation carrying a missense variant in CACNB2 as well as from three healthy independent persons. These cells (hiPSC-CMs) generated from skin biopsies of healthy persons and the BrS patient (BrS-hiPSC-CMs) as well as CRISPR/Cas9 corrected cells (isogenic control, site-variant corrected) were used for this study. The hiPSC-CMs from the BrS patient showed a significantly reduced L-type calcium channel current (ICa-L) compared with the healthy control hiPSC-CMs. The inactivation curve was shifted to a more positive potential and the recovery from inactivation was accelerated. The protein expression of CACNB2 of the hiPSC-CMs from the BrS-patient was significantly decreased compared with healthy hiPSC-CMs. Moreover, the correction of the CACNB2 site-variant rescued the changes seen in the hiPSC-CMs of the BrS patient to the normal state. These data indicate that the CACNB2 gene variant led to loss-of-function of L-type calcium channels in hiPSC-CMs from the BrS patient. Strikingly, arrhythmia events were more frequently detected in BrS-hiPSC-CMs. Bisoprolol (beta-blockers) at low concentration and quinidine decreased arrhythmic events. Conclusions: The CACNB2 variant (c.425C > T/p.S142F) causes a loss-of-function of L-type calcium channels and is pathogenic for this type of BrS. Bisoprolol and quinidine may be effective for treating BrS with this variant.
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- 2022
28. Decoding Functional High-Density Lipoprotein Particle Surfaceome Interactions
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Kathrin Frey, Sandra Goetze, Lucia Rohrer, Arnold von Eckardstein, Bernd Wollscheid, University of Zurich, Goetze, Sandra, and Wollscheid, Bernd
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Vascular Endothelial Growth Factor A ,HDL ,1503 Catalysis ,1607 Spectroscopy ,Receptors, Cell Surface ,610 Medicine & health ,spatial proteotyping ,Ligands ,540 Chemistry ,1312 Molecular Biology ,1706 Computer Science Applications ,Humans ,10038 Institute of Clinical Chemistry ,Receptors, Scavenger ,molecular health ,signaling ,surfaceome ,receptome ,ligand-receptor interactions ,chemoproteomics ,c-Mer Tyrosine Kinase ,1604 Inorganic Chemistry ,Lipoproteins, HDL ,1606 Physical and Theoretical Chemistry ,1605 Organic Chemistry - Abstract
High-density lipoprotein (HDL) is a mixture of complex particles mediating reverse cholesterol transport (RCT) and several cytoprotective activities. Despite its relevance for human health, many aspects of HDL-mediated lipid trafficking and cellular signaling remain elusive at the molecular level. During HDL's journey throughout the body, its functions are mediated through interactions with cell surface receptors on different cell types. To characterize and better understand the functional interplay between HDL particles and tissue, we analyzed the surfaceome-residing receptor neighborhoods with which HDL potentially interacts. We applied a combination of chemoproteomic technologies including automated cell surface capturing (auto-CSC) and HATRIC-based ligand-receptor capturing (HATRIC-LRC) on four different cellular model systems mimicking tissues relevant for RCT. The surfaceome analysis of EA.hy926, HEPG2, foam cells, and human aortic endothelial cells (HAECs) revealed the main currently known HDL receptor scavenger receptor B1 (SCRB1), as well as 155 shared cell surface receptors representing potential HDL interaction candidates. Since vascular endothelial growth factor A (VEGF-A) was recently found as a regulatory factor of transendothelial transport of HDL, we next analyzed the VEGF-modulated surfaceome of HAEC using the auto-CSC technology. VEGF-A treatment led to the remodeling of the surfaceome of HAEC cells, including the previously reported higher surfaceome abundance of SCRB1. In total, 165 additional receptors were found on HAEC upon VEGF-A treatment representing SCRB1 co-regulated receptors potentially involved in HDL function. Using the HATRIC-LRC technology on human endothelial cells, we specifically aimed for the identification of other bona fide (co-)receptors of HDL beyond SCRB1. HATRIC-LRC enabled, next to SCRB1, the identification of the receptor tyrosine-protein kinase Mer (MERTK). Through RNA interference, we revealed its contribution to endothelial HDL binding and uptake. Furthermore, subsequent proximity ligation assays (PLAs) demonstrated the spatial vicinity of MERTK and SCRB1 on the endothelial cell surface. The data shown provide direct evidence for a complex and dynamic HDL receptome and that receptor nanoscale organization may influence binding and uptake of HDL., International Journal of Molecular Sciences, 23 (16), ISSN:1422-0067
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- 2022
29. Development of Neurogenic Detrusor Overactivity after Thoracic Spinal Cord Injury Is Accompanied by Time-Dependent Changes in Lumbosacral Expression of Axonal Growth Regulators
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Sílvia Sousa Chambel, Ana Ferreira, Raquel Oliveira, Rafael Miranda, Luís Vale, Carlos Reguenga, Martin E. Schwab, Célia Duarte Cruz, University of Zurich, and Cruz, Célia Duarte
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1503 Catalysis ,Nogo Proteins ,1607 Spectroscopy ,610 Medicine & health ,spinal cord injury ,repulsive molecules ,axonal growth ,bladder dysfunction ,neurogenic detrusor overactivity ,Catalysis ,Inorganic Chemistry ,Ganglia, Spinal ,1312 Molecular Biology ,1706 Computer Science Applications ,Animals ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy ,Spinal Cord Injuries ,1604 Inorganic Chemistry ,Urinary Bladder, Overactive ,Organic Chemistry ,General Medicine ,11359 Institute for Regenerative Medicine (IREM) ,Computer Science Applications ,Rats ,Chondroitin Sulfate Proteoglycans ,Spinal Cord ,Quality of Life ,1606 Physical and Theoretical Chemistry ,1605 Organic Chemistry - Abstract
Thoracic spinal cord injury (SCI) results in urinary dysfunction, which majorly affects the quality of life of SCI patients. Abnormal sprouting of lumbosacral bladder afferents plays a crucial role in this condition. Underlying mechanisms may include changes in expression of regulators of axonal growth, including chondroitin sulphate proteoglycans (CSPGs), myelin-associated inhibitors (MAIs) and repulsive guidance molecules, known to be upregulated at the injury site post SCI. Here, we confirmed lumbosacral upregulation of the growth-associated protein GAP43 in SCI animals with bladder dysfunction, indicating the occurrence of axonal sprouting. Neurocan and Phosphacan (CSPGs), as well as Nogo-A (MAI), at the same spinal segments were upregulated 7 days post injury (dpi) but returned to baseline values 28 dpi. In turn, qPCR analysis of the mRNA levels for receptors of those repulsive molecules in dorsal root ganglia (DRG) neurons showed a time-dependent decrease in receptor expression. In vitro assays with DRG neurons from SCI rats demonstrated that exposure to high levels of NGF downregulated the expression of some, but not all, receptors for those regulators of axonal growth. The present results, therefore, show significant molecular changes at the lumbosacral cord and DRGs after thoracic lesion, likely critically involved in neuroplastic events leading to urinary impairment.
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- 2022
30. Structure-Activity Relationships for 5' Modifications of 4,5-Aminoglycoside Antibiotics
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Quirke, Jonathan C K, Sati, Girish C, Sonousi, Amr, Gysin, Marina, Haldimann, Klara, Böttger, Erik C, Vasella, Andrea, Hobbie, Sven N, Crich, David, University of Zurich, and Crich, David
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1303 Biochemistry ,3004 Pharmacology ,10179 Institute of Medical Microbiology ,1313 Molecular Medicine ,3002 Drug Discovery ,570 Life sciences ,biology ,610 Medicine & health ,3000 General Pharmacology, Toxicology and Pharmaceutics ,1605 Organic Chemistry - Published
- 2022
31. In Vitro and Ectopic In Vivo Studies toward the Utilization of Rapidly Isolated Human Nasal Chondrocytes for Single-Stage Arthroscopic Cartilage Regeneration Therapy
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Gyözö Lehoczky, Raluca Elena Trofin, Queralt Vallmajo-Martin, Shikha Chawla, Karoliina Pelttari, Marcus Mumme, Martin Haug, Christian Egloff, Marcel Jakob, Martin Ehrbar, Ivan Martin, Andrea Barbero, University of Zurich, and Martin, Ivan
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1503 Catalysis ,1604 Inorganic Chemistry ,Organic Chemistry ,1607 Spectroscopy ,610 Medicine & health ,General Medicine ,Catalysis ,Computer Science Applications ,Inorganic Chemistry ,1312 Molecular Biology ,1706 Computer Science Applications ,Physical and Theoretical Chemistry ,1606 Physical and Theoretical Chemistry ,Molecular Biology ,10026 Clinic for Obstetrics ,Spectroscopy ,cartilage regeneration ,autologous chondrocyte implantation ,nasal chondrocytes ,single-stage ,arthroscopy ,tissue engineering ,polyethylene glycol ,hydrogel ,platelet lysate ,1605 Organic Chemistry - Abstract
Nasal chondrocytes (NCs) have a higher and more reproducible chondrogenic capacity than articular chondrocytes, and the engineered cartilage tissue they generate in vitro has been demonstrated to be safe in clinical applications. Here, we aimed at determining the feasibility for a single-stage application of NCs for cartilage regeneration under minimally invasive settings. In particular, we assessed whether NCs isolated using a short collagenase digestion protocol retain their potential to proliferate and chondro-differentiate within an injectable, swiftly cross-linked and matrix-metalloproteinase (MMP)-degradable polyethylene glycol (PEG) gel enriched with human platelet lysate (hPL). NC-hPL-PEG gels were additionally tested for their capacity to generate cartilage tissue in vivo and to integrate into cartilage/bone compartments of human osteochondral plugs upon ectopic subcutaneous implantation into nude mice. NCs isolated with a rapid protocol and embedded in PEG gels with hPL at low cell density were capable of efficiently proliferating and of generating tissue rich in glycosaminoglycans and collagen II. NC-hPL-PEG gels developed into hyaline-like cartilage tissues upon ectopic in vivo implantation and integrated with surrounding native cartilage and bone tissues. The delivery of NCs in PEG gels containing hPL is a feasible strategy for cartilage repair and now requires further validation in orthotopic in vivo models.
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- 2022
32. Early Molecular Insights into Thanatin Analogues Binding to A. baumannii LptA
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Oi, Kathryn K, Moehle, Kerstin, Schuster, Matthias, Zerbe, Oliver, University of Zurich, and Zerbe, Oliver
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10120 Department of Chemistry ,Gram-negative bacteria ,antimicrobial resistance ,A. baumannii ,LPS transport ,LptA ,thanatin ,thanatin analogues ,NMR structure ,binding constants ,1602 Analytical Chemistry ,1601 Chemistry (miscellaneous) ,3002 Drug Discovery ,Organic Chemistry ,3003 Pharmaceutical Science ,Pharmaceutical Science ,Analytical Chemistry ,Chemistry (miscellaneous) ,1313 Molecular Medicine ,540 Chemistry ,Drug Discovery ,Molecular Medicine ,Physical and Theoretical Chemistry ,1606 Physical and Theoretical Chemistry ,1605 Organic Chemistry - Abstract
The cationic antimicrobial ß-hairpin, thanatin, was recently developed into drug-like analogues active against carbapenem-resistant Enterobacteriaceae (CRE). The analogues represent new antibiotics with a novel mode of action targeting LptA in the periplasm and disrupting LPS transport. The compounds lose antimicrobial efficacy when the sequence identity to E. coli LptA falls below 70%. We wanted to test the thanatin analogues against LptA of a phylogenetic distant organism and investigate the molecular determinants of inactivity. Acinetobacter baumannii (A. baumannii) is a critical Gram-negative pathogen that has gained increasing attention for its multi-drug resistance and hospital burden. A. baumannii LptA shares 28% sequence identity with E. coli LptA and displays an intrinsic resistance to thanatin and thanatin analogues (MIC values > 32 µg/mL) through a mechanism not yet described. We investigated the inactivity further and discovered that these CRE-optimized derivatives can bind to LptA of A. baumannii in vitro, despite the high MIC values. Herein, we present a high-resolution structure of A. baumannii LptAm in complex with a thanatin derivative 7 and binding affinities of selected thanatin derivatives. Together, these data offer structural insights into why thanatin derivatives are inactive against A. baumannii LptA, despite binding events in vitro.
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- 2023
33. Cyclic Octapeptides Composed of Two Glutathione Units Outperform the Monomer in Lead Detoxification
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Sauser, Luca, Kalvoda, Tadeáš, Kavas, Ayça, Rulíšek, Lubomír, Shoshan, Michal S, University of Zurich, and Shoshan, Michal S
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10120 Department of Chemistry ,Pharmacology ,1303 Biochemistry ,3002 Drug Discovery ,Organic Chemistry ,Toxicology and Pharmaceutics ,Glutathione ,Biochemistry ,3000 General Pharmacology, Toxicology and Pharmaceutics ,Antioxidants ,3004 Pharmacology ,Lead ,1313 Molecular Medicine ,540 Chemistry ,General Pharmacology ,Drug Discovery ,Humans ,Molecular Medicine ,General Pharmacology, Toxicology and Pharmaceutics ,1605 Organic Chemistry ,Chelating Agents - Abstract
A rationally-designed scaffold of cyclic octapeptides composed of two units of the natural tripeptide glutathione (GSH) was optimized to strongly and selectively capture toxic lead ions (Pb(II)). Using state-of-the-art computational tools, a list of eleven plausible peptides was shortened to five analogs based on their calculated affinity to Pb(II) ions. We then synthesized and investigated them for their abilities to recover Pb-poisoned human cells. A clear pattern was observed from the in vitro detoxification results, indicating the importance of cavity size and polar moieties to enhance metal capturing. These, together with the apparent benefit of cyclizing the peptides, improved the detoxification of the two lead peptides by approximately two folds compared to GSH and the benchmark chelating agents against Pb poisoning. Moreover, the two peptides did not show any toxicity and, therefore, were thoroughly investigated to determine their potential as next-generation remedies for Pb poisoning.
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- 2022
34. Synthesis and evaluation of 1,2,3-dithiazole inhibitors of the nucleocapsid protein of feline immunodeficiency virus (FIV) as a model for HIV infection
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Laitinen, Tuomo, Meili, Theres, Koyioni, Maria, Koutentis, Panayiotis A, Poso, Antti, Hofmann-Lehmann, Regina, Asquith, Christopher R M, University of Zurich, and Asquith, Christopher R M
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1303 Biochemistry ,3002 Drug Discovery ,Organic Chemistry ,Clinical Biochemistry ,3003 Pharmaceutical Science ,Pharmaceutical Science ,610 Medicine & health ,HIV Infections ,1308 Clinical Biochemistry ,Immunodeficiency Virus, Feline ,Nucleocapsid Proteins ,Biochemistry ,Antiviral Agents ,Structure-Activity Relationship ,1313 Molecular Medicine ,Drug Discovery ,11404 Department of Clinical Diagnostics and Services ,1312 Molecular Biology ,Cats ,Molecular Medicine ,Animals ,11434 Center for Clinical Studies ,Molecular Biology ,1605 Organic Chemistry - Abstract
We disclose a series of potent anti-viral 1,2,3-dithiazoles, accessed through a succinct synthetic approach from 4,5-dichloro-1,2,3-dithiazolium chloride (Appel's salt). A series of small libraries of compounds were screened against feline immunodeficiency virus (FIV) infected cells as a model for HIV. This approach highlighted new structure activity relationship understanding and led to the development of sub-micro molar anti-viral compounds with reduced toxicity. In addition, insight into the mechanistic progress of this system is provided via advanced QM-MM modelling. The 1,2,3-dithiazole represents a versatile scaffold with potential for further development to treat both FIV and HIV.
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- 2022
35. Placental Passage of Protopine in an Ex Vivo Human Perfusion System
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Spiess, Deborah, Abegg, Vanessa Fabienne, Chauveau, Antoine, Treyer, Andrea, Reinehr, Michael, Oufir, Mouhssin, Duong, Elisa, Potterat, Olivier, Hamburger, Matthias, Simões-Wüst, Ana Paula, University of Zurich, and Simões-Wüst, Ana Paula
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Pharmacology ,1602 Analytical Chemistry ,3002 Drug Discovery ,Organic Chemistry ,3003 Pharmaceutical Science ,2707 Complementary and Alternative Medicine ,Pharmaceutical Science ,610 Medicine & health ,Analytical Chemistry ,3004 Pharmacology ,Complementary and alternative medicine ,10049 Institute of Pathology and Molecular Pathology ,1313 Molecular Medicine ,Drug Discovery ,Molecular Medicine ,10026 Clinic for Obstetrics ,1605 Organic Chemistry - Abstract
The placental passage of protopine was investigated with a human ex vivo placental perfusion model. The model was first validated with diazepam and citalopram, 2 compounds known to cross the placental barrier, and antipyrine as a positive control. All compounds were quantified by partially validated U(H)PLC-MS/MS bioanalytical methods. Protopine was transferred from the maternal to the fetal circuit, with a steady-state reached after 90 min. The study compound did not affect placental viability or functionality, as glucose consumption, lactate production, and beta-human chorionic gonadotropin, and leptin release remained constant. Histopathological evaluation of all placental specimens showed unremarkable, age-appropriate parenchymal maturation with no pathologic findings.
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- 2022
36. Identification of Key Factors for Anoxic Survival of B. cenocepacia H111
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Paszti, Sarah, Vitale, Alessandra, Liu, Yilei, Braunwalder, Rubina, Kalawong, Ratchara, Biner, Olivier, Pessi, Gabriella, Eberl, Leo, University of Zurich, Pessi, Gabriella, and Eberl, Leo
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1503 Catalysis ,1604 Inorganic Chemistry ,Organic Chemistry ,1607 Spectroscopy ,General Medicine ,580 Plants (Botany) ,Catalysis ,Computer Science Applications ,Inorganic Chemistry ,10126 Department of Plant and Microbial Biology ,1312 Molecular Biology ,1706 Computer Science Applications ,Burkholderia cenocepacia H111 ,Bcc ,cystic fibrosis ,Tn-seq ,anoxic survival ,Galleria mellonella ,virulence factors ,10211 Zurich-Basel Plant Science Center ,Physical and Theoretical Chemistry ,1606 Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy ,1605 Organic Chemistry - Abstract
Burkholderia cenocepacia is an opportunistic pathogen that can lead to severe infections in patients suffering from cystic fibrosis (CF) and chronic granulomatous disease. Being an obligate aerobe, B. cenocepacia is unable to grow in the absence of oxygen. In this study, we show that the CF isolate B. cenocepacia H111 can survive in the absence of oxygen. Using a transposon sequencing (Tn-seq) approach, we identified 71 fitness determinants involved in anoxic survival, including a Crp-Fnr family transcriptional regulatory gene (anr2), genes coding for the sensor kinase RoxS and its response regulator RoxR, the sigma factor for flagella biosynthesis (FliA) and subunits of a cytochrome bd oxidase (CydA, CydB and the potentially novel subunit CydP). Individual knockouts of these fitness determinants significantly reduced anoxic survival, and inactivation of both anr copies is shown to be lethal under anoxic conditions. We also show that the two-component system RoxS/RoxR and FliA are important for virulence and swarming/swimming, respectively.
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- 2022
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37. Structure‐Activity Studies of Nitroreductase‐Responsive Near‐Infrared Heptamethine Cyanine Fluorescent Probes
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Morsby, Janeala J, Atkinson, Kirk M, Shradha Reddy Kommidi, Sai, Freel, Tristan, Janeková, Hana, Stacko, Peter, Smith, Bradley D, University of Zurich, Stacko, Peter, and Smith, Bradley D
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10120 Department of Chemistry ,540 Chemistry ,Organic Chemistry ,Physical and Theoretical Chemistry ,1606 Physical and Theoretical Chemistry ,1605 Organic Chemistry - Published
- 2022
38. Stereoselective Syntheses of Deuterated Pipecolic Acids as Tools to Investigate the Stereoselectivity of the Hydroxylase GetF
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Nadine Neis, Feng Xie, Daniel Krug, Haowen Zhao, Andreas Siebert, Tina M. Binz, Chengzhang Fu, Rolf Müller, Uli Kazmaier, University of Zurich, and Kazmaier, Uli
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Synthetic methods ,Claisen rearrangement ,Organic Chemistry ,Hydroxylases ,340 Law ,610 Medicine & health ,Physical and Theoretical Chemistry ,Biosynthesis ,Deuterium ,1606 Physical and Theoretical Chemistry ,10218 Institute of Legal Medicine ,1605 Organic Chemistry - Published
- 2022
39. Structure–Photoreactivity Relationship of 3-Hydroxyflavone-Based CO-Releasing Molecules
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Marina Russo, Vojtěch Orel, Peter Štacko, Mária Šranková, Lucie Muchová, Libor Vítek, Petr Klán, University of Zurich, and Klán, Petr
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Flavonoids ,10120 Department of Chemistry ,Carbon Monoxide ,Spectrum Analysis ,540 Chemistry ,Organic Chemistry ,1605 Organic Chemistry - Abstract
Carbon monoxide (CO) is an endogenous signaling molecule that regulates diverse physiological processes. The therapeutic potential of CO is hampered by its intrinsic toxicity, and its administration poses a significant challenge. Photoactivatable CO-releasing molecules (photoCORMs) are an excellent tool to overcome the side effects of untargeted CO administration and provide precise spatial and temporal control over its release. Here, we studied the CO release mechanism of a small library of derivatives based on 3-hydroxy-2-phenyl-4
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- 2022
40. Dysregulated expression of arterial microRNAs and their target gene networks in temporal arteries of treatment-naïve patients with giant cell arteritis
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Vesna Jurčić, Mojca Frank-Bertoncelj, Žiga Rotar, Katja Lakota, S. Sodin-Šemrl, Oliver Distler, Alojzija Hočevar, Tadeja Kuret, Saša Čučnik, University of Zurich, and Frank-Bertoncelj, Mojca
- Subjects
0301 basic medicine ,Pathology ,MMP2 ,preoblikovanje arterij ,arterial ultrasound ,Biopsy ,1607 Spectroscopy ,microRNA-target genes ,MMP9 ,0302 clinical medicine ,mikroRNA ,Gene Regulatory Networks ,Biology (General) ,skin and connective tissue diseases ,velikanski celični arteritis ,Spectroscopy ,TIMP1 ,Ultrasonography ,microRNA ,10051 Rheumatology Clinic and Institute of Physical Medicine ,toll-like receptor signaling ,General Medicine ,Immunohistochemistry ,vision disturbances ,Computer Science Applications ,Temporal Arteries ,Vascular endothelial growth factor A ,Chemistry ,KLF4 ,cardiovascular system ,RNA Interference ,Disease Susceptibility ,Symptom Assessment ,1606 Physical and Theoretical Chemistry ,medicine.medical_specialty ,1503 Catalysis ,QH301-705.5 ,610 Medicine & health ,Biology ,Catalysis ,Article ,Inorganic Chemistry ,arterial remodelling ,03 medical and health sciences ,Kruppel-Like Factor 4 ,medicine ,1312 Molecular Biology ,1706 Computer Science Applications ,Humans ,Arteritis ,RNA, Messenger ,cardiovascular diseases ,Physical and Theoretical Chemistry ,Molecular Biology ,QD1-999 ,030203 arthritis & rheumatology ,1604 Inorganic Chemistry ,giant cell arteritis ,Gene Expression Profiling ,Organic Chemistry ,medicine.disease ,udc:616-002 ,Giant cell arteritis ,MicroRNAs ,030104 developmental biology ,Gene Expression Regulation ,Biomarkers ,1605 Organic Chemistry - Abstract
In this study, we explored expression of microRNA (miR), miR-target genes and matrix remodelling molecules in temporal artery biopsies (TABs) from treatment-naïve patients with giant cell arteritis (GCA, n = 41) and integrated these analyses with clinical, laboratory, ultrasound and histological manifestations of GCA. NonGCA patients (n = 4) served as controls. GCA TABs exhibited deregulated expression of several miRs (miR-21-5p, -145-5p, -146a-5p, -146b-5p, -155-5p, 424-3p, -424-5p, -503-5p), putative miR-target genes (YAP1, PELI1, FGF2, VEGFA, KLF4) and matrix remodelling factors (MMP2, MMP9, TIMP1, TIPM2) with key roles in Toll-like receptor signaling, mechanotransduction and extracellular matrix biology. MiR-424-3p, -503-5p, KLF4, PELI1 and YAP1 were identified as new deregulated molecular factors in GCA TABs. Quantities of miR-146a-5p, YAP1, PELI1, FGF2, TIMP2 and MMP9 were particularly high in histologically positive GCA TABs with occluded temporal artery lumen. MiR-424-5p expression in TABs and the presence of facial or carotid arteritis on ultrasound were associated with vision disturbances in GCA patients. Correlative analysis of miR-mRNA quantities demonstrated a highly interrelated expression network of deregulated miRs and mRNAs in temporal arteries and identified KLF4 as a candidate target gene of deregulated miR-21-5p, -146a-5p and -155-5p network in GCA TABs. Meanwhile, arterial miR and mRNA expression did not correlate with constitutive symptoms and signs of GCA, elevated markers of systemic inflammation nor sonographic characteristics of GCA. Our study provides new insights into GCA pathophysiology and uncovers new candidate biomarkers of vision impairment in GCA.
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- 2022
41. Coordination Chemistry of Nucleotides and Antivirally Active Acyclic Nucleoside Phosphonates, including Mechanistic Considerations
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Sigel, Astrid, Sigel, Helmut, Sigel, Roland K O, University of Zurich, Sigel, Helmut, and Sigel, Roland K O
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10120 Department of Chemistry ,1601 Chemistry (miscellaneous) ,3003 Pharmaceutical Science ,Organophosphonates ,Pharmaceutical Science ,Antiviral Agents ,Analytical Chemistry ,Phosphates ,Adenosine Triphosphate ,540 Chemistry ,Drug Discovery ,Physical and Theoretical Chemistry ,Chelating Agents ,Ions ,1602 Analytical Chemistry ,Nucleotides ,3002 Drug Discovery ,Adenine ,Organic Chemistry ,Nucleosides ,Adenosine Monophosphate ,Oxygen ,Chemistry (miscellaneous) ,Metals ,1313 Molecular Medicine ,Molecular Medicine ,1606 Physical and Theoretical Chemistry ,Sugars ,1605 Organic Chemistry ,Ethers - Abstract
Considering that practically all reactions that involve nucleotides also involve metal ions, it is evident that the coordination chemistry of nucleotides and their derivatives is an essential corner stone of biological inorganic chemistry. Nucleotides are either directly or indirectly involved in all processes occurring in Nature. It is therefore no surprise that the constituents of nucleotides have been chemically altered—that is, at the nucleobase residue, the sugar moiety, and also at the phosphate group, often with the aim of discovering medically useful compounds. Among such derivatives are acyclic nucleoside phosphonates (ANPs), where the sugar moiety has been replaced by an aliphatic chain (often also containing an ether oxygen atom) and the phosphate group has been replaced by a phosphonate carrying a carbon–phosphorus bond to make the compounds less hydrolysis-sensitive. Several of these ANPs show antiviral activity, and some of them are nowadays used as drugs. The antiviral activity results from the incorporation of the ANPs into the growing nucleic acid chain—i.e., polymerases accept the ANPs as substrates, leading to chain termination because of the missing 3′-hydroxyl group. We have tried in this review to describe the coordination chemistry (mainly) of the adenine nucleotides AMP and ATP and whenever possible to compare it with that of the dianion of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA2− = adenine(N9)-CH2-CH2-O-CH2-PO32) [or its diphosphate (PMEApp4−)] as a representative of the ANPs. Why is PMEApp4− a better substrate for polymerases than ATP4−? There are three reasons: (i) PMEA2− with its anti-like conformation (like AMP2−) fits well into the active site of the enzyme. (ii) The phosphonate group has an enhanced metal ion affinity because of its increased basicity. (iii) The ether oxygen forms a 5-membered chelate with the neighboring phosphonate and favors thus coordination at the Pα group. Research on ANPs containing a purine residue revealed that the kind and position of the substituent at C2 or C6 has a significant influence on the biological activity. For example, the shift of the (C6)NH2 group in PMEA to the C2 position leads to 9-[2-(phosphonomethoxy)ethyl]-2-aminopurine (PME2AP), an isomer with only a moderate antiviral activity. Removal of (C6)NH2 favors N7 coordination, e.g., of Cu2+, whereas the ether O atom binding of Cu2+ in PMEA facilitates N3 coordination via adjacent 5- and 7-membered chelates, giving rise to a Cu(PMEA)cl/O/N3 isomer. If the metal ions (M2+) are M(α,β)-M(γ)-coordinated at a triphosphate chain, transphosphorylation occurs (kinases, etc.), whereas metal ion binding in a M(α)-M(β,γ)-type fashion is relevant for polymerases. It may be noted that with diphosphorylated PMEA, (PMEApp4−), the M(α)-M(β,γ) binding is favored because of the formation of the 5-membered chelate involving the ether O atom (see above). The self-association tendency of purines leads to the formation of dimeric [M2(ATP)]2(OH)− stacks, which occur in low concentration and where one half of the molecule undergoes the dephosphorylation reaction and the other half stabilizes the structure—i.e., acts as the “enzyme” by bridging the two ATPs. In accord herewith, one may enhance the reaction rate by adding AMP2− to the [Cu2(ATP)]2(OH)− solution, as this leads to the formation of mixed stacked Cu3(ATP)(AMP)(OH)− species, in which AMP2− takes over the structuring role, while the other “half” of the molecule undergoes dephosphorylation. It may be added that Cu3(ATP)(PMEA) or better Cu3(ATP)(PMEA)(OH)− is even a more reactive species than Cu3(ATP)(AMP)(OH)−. – The matrix-assisted self-association and its significance for cell organelles with high ATP concentrations is summarized and discussed, as is, e.g., the effect of tryptophanate (Trp−), which leads to the formation of intramolecular stacks in M(ATP)(Trp)3− complexes (formation degree about 75%). Furthermore, it is well-known that in the active-site cavities of enzymes the dielectric constant, compared with bulk water, is reduced; therefore, we have summarized and discussed the effect of a change in solvent polarity on the stability and structure of binary and ternary complexes: Opposite effects on charged O sites and neutral N sites are observed, and this leads to interesting insights.
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- 2022
42. Regulation of ABCA1 by AMD-Associated Genetic Variants and Hypoxia in iPSC-RPE
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Peters, Florian, Ebner, Lynn J A, Atac, David, Maggi, Jordi, Berger, Wolfgang, den Hollander, Anneke I, Grimm, Christian, University of Zurich, Peters, Florian, and Grimm, Christian
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10018 Ophthalmology Clinic ,11124 Institute of Medical Molecular Genetics ,1503 Catalysis ,1604 Inorganic Chemistry ,1312 Molecular Biology ,1706 Computer Science Applications ,570 Life sciences ,biology ,1607 Spectroscopy ,610 Medicine & health ,1606 Physical and Theoretical Chemistry ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,1605 Organic Chemistry - Abstract
Contains fulltext : 252024.pdf (Publisher’s version ) (Open Access) Age-related macular degeneration (AMD) is a progressive disease of the macula characterized by atrophy of the retinal pigment epithelium (RPE) and photoreceptor degeneration, leading to severe vision loss at advanced stages in the elderly population. Impaired reverse cholesterol transport (RCT) as well as intracellular lipid accumulation in the RPE are implicated in AMD pathogenesis. Here, we focus on ATP-binding cassette transporter A1 (ABCA1), a major cholesterol transport protein in the RPE, and analyze conditions that lead to ABCA1 dysregulation in induced pluripotent stem cell (iPSC)-derived RPE cells (iRPEs). Our results indicate that the risk-conferring alleles rs1883025 (C) and rs2740488 (A) in ABCA1 are associated with increased ABCA1 mRNA and protein levels and reduced efficiency of cholesterol efflux from the RPE. Hypoxia, an environmental risk factor for AMD, reduced expression of ABCA1 and increased intracellular lipid accumulation. Treatment with a liver X receptor (LXR) agonist led to an increase in ABCA1 expression and reduced lipid accumulation. Our data strengthen the homeostatic role of cholesterol efflux in the RPE and suggest that increasing cellular cholesterol export by stimulating ABCA1 expression might lessen lipid load, improving RPE survival and reducing the risk of developing AMD.
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- 2022
43. Polar Substituents Enable Efficient Catalysis for a Class of Cobalt Polypyridyl Hydrogen Evolving Catalysts
- Author
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Peter Müller, Benjamin Probst, Bernhard Spingler, Olivier Blacque, Roger Alberto, University of Zurich, and Alberto, Roger
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10120 Department of Chemistry ,1303 Biochemistry ,1503 Catalysis ,1604 Inorganic Chemistry ,3002 Drug Discovery ,UFSP13-6 Solar Light to Chemical Energy Conversion ,Organic Chemistry ,Biochemistry ,Catalysis ,Inorganic Chemistry ,540 Chemistry ,Drug Discovery ,Physical and Theoretical Chemistry ,1606 Physical and Theoretical Chemistry ,1605 Organic Chemistry - Published
- 2022
44. Highly Phototoxic Transplatin‐Modified Distyryl‐BODIPY Photosensitizers for Photodynamic Therapy
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Padrutt, Roxane, Babu, Vipin, Klingler, Simon, Kalt, Martina, Schumer, Frank, Anania, Maria I, Schneider, Lukas, Spingler, Bernhard, University of Zurich, and Spingler, Bernhard
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Boron Compounds ,10120 Department of Chemistry ,1303 Biochemistry ,Cell Survival ,medicine.medical_treatment ,Antineoplastic Agents ,Photodynamic therapy ,Photochemistry ,Toxicology and Pharmaceutics ,01 natural sciences ,Biochemistry ,3000 General Pharmacology, Toxicology and Pharmaceutics ,Structure-Activity Relationship ,chemistry.chemical_compound ,540 Chemistry ,General Pharmacology ,Drug Discovery ,medicine ,Humans ,Photosensitizer ,General Pharmacology, Toxicology and Pharmaceutics ,Cell Proliferation ,Pharmacology ,Photosensitizing Agents ,Dose-Response Relationship, Drug ,Molecular Structure ,Singlet Oxygen ,010405 organic chemistry ,Chemistry ,Singlet oxygen ,3002 Drug Discovery ,Organic Chemistry ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,3004 Pharmacology ,Intersystem crossing ,Photochemotherapy ,1313 Molecular Medicine ,Intramolecular force ,Molecular Medicine ,Cisplatin ,Drug Screening Assays, Antitumor ,BODIPY ,Phototoxicity ,HeLa Cells ,1605 Organic Chemistry - Abstract
We report the synthesis of the first transplatin-BODIPY conjugates for application in photodynamic therapy (PDT). The distyryl BODIPYs containing two iodine atoms were designed to absorb in the red region, easily undergo intersystem crossing for efficient singlet oxygen generation, and additionally offer the possibility for coordination with mono-activated transplatin. We were able to demonstrate that coordination of the BODIPYs with a mono-activated transplatin increases the phototoxic index of the photosensitizers significantly, giving rise to highly phototoxic distyryl BODIPY derivatives, of which one was shown to have the highest ever reported phototoxic index against any cell line. Furthermore, the photophysical mechanism of singlet oxygen generation in distyryl BODIPYs undergoing intramolecular charge transfer was studied experimentally and using time-dependent density functional theory.
- Published
- 2020
45. Green Algae as a Drug Delivery System for the Controlled Release of Antibiotics
- Author
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Shchelik, Inga S, Sieber, Simon, Gademann, Karl, University of Zurich, and Gademann, Karl
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10120 Department of Chemistry ,1503 Catalysis ,medicine.drug_class ,Antibiotics ,Chlamydomonas reinhardtii ,010402 general chemistry ,01 natural sciences ,antibiotics ,Catalysis ,Microbiology ,Chlorophyta ,Vancomycin ,540 Chemistry ,Generally recognized as safe ,medicine ,drug delivery system ,photocleavage ,biology ,010405 organic chemistry ,Chemistry ,Communication ,Organic Chemistry ,General Chemistry ,biology.organism_classification ,Controlled release ,Communications ,Anti-Bacterial Agents ,0104 chemical sciences ,Delayed-Action Preparations ,Drug delivery ,Drug Delivery ,controlled release ,Drug carrier ,Bacteria ,1605 Organic Chemistry ,medicine.drug - Abstract
New strategies to efficiently treat bacterial infections are crucial to circumvent the increase of resistant strains and to mitigate side effects during treatment. Skin and soft tissue infections represent one of the areas suffering the most from these resistant strains. We developed a new drug delivery system composed of the green algae, Chlamydomonas reinhardtii, which is generally recognized as safe, to target specifically skin diseases. A two‐step functionalization strategy was used to chemically modify the algae with the antibiotic vancomycin. Chlamydomonas reinhardtii was found to mask vancomycin and the insertion of a photocleavable linker was used for the release of the antibiotic. This living drug carrier was evaluated in presence of Bacillus subtilis and, only upon UVA1‐mediated release, growth inhibition of bacteria was observed. These results represent one of the first examples of a living organism used as a drug delivery system for the release of an antibiotic by UVA1‐irradiation., Algae control the release: A new approach for antibiotic caging and controlled release was developed using Chlamydomonas reinhardtii. The algae were covalently modified with vancomycin, and using a photocleavable linker, light‐mediated release of an antibacterial agent from the cell surface and inhibited the growth of Bacillus subtilis (see figure).
- Published
- 2020
46. Should Degenerated Intervertebral Discs of Patients with Modic Type 1 Changes Be Treated with Mesenchymal Stem Cells?
- Author
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Herger, Nick, Bermudez-Lekerika, Paola, Farshad, Mazda, Albers, Christoph E, Distler, Oliver, Gantenbein, Benjamin, Dudli, Stefan, University of Zurich, and Dudli, Stefan
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1503 Catalysis ,1607 Spectroscopy ,610 Medicine & health ,Intervertebral Disc Degeneration ,Catalysis ,Inorganic Chemistry ,Bone Marrow ,1312 Molecular Biology ,1706 Computer Science Applications ,Humans ,Physical and Theoretical Chemistry ,Intervertebral Disc ,Molecular Biology ,Spectroscopy ,1604 Inorganic Chemistry ,Organic Chemistry ,10051 Rheumatology Clinic and Institute of Physical Medicine ,Mesenchymal Stem Cells ,General Medicine ,equipment and supplies ,Computer Science Applications ,570 Life sciences ,biology ,1606 Physical and Theoretical Chemistry ,Low Back Pain ,1605 Organic Chemistry - Abstract
Low back pain (LBP) has been among the leading causes of disability for the past 30 years. This highlights the need for improvement in LBP management. Many clinical trials focus on developing treatments against degenerative disc disease (DDD). The multifactorial etiology of DDD and associated risk factors lead to a heterogeneous patient population. It comes as no surprise that the outcomes of clinical trials on intradiscal mesenchymal stem cell (MSC) injections for patients with DDD are inconsistent. Intradiscal MSC injections have demonstrated substantial pain relief and significant disability-related improvements, yet they have failed to regenerate the intervertebral disc (IVD). Increasing evidence suggests that the positive outcomes in clinical trials might be attributed to the immunomodulatory potential of MSCs rather than to their regenerative properties. Therefore, patient stratification for inflammatory DDD phenotypes may (i) better serve the mechanisms of action of MSCs and (ii) increase the treatment effect. Modic type 1 changes—pathologic inflammatory, fibrotic changes in the vertebral bone marrow—are frequently observed adjacent to degenerated IVDs in chronic LBP patients and represent a clinically distinct subpopulation of patients with DDD. This review discusses whether degenerated IVDs of patients with Modic type 1 changes should be treated with an intradiscal MSC injection.
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- 2022
47. Synthesis of Ionizable Calix[4]arenes for Chelation of Selected Divalent Cations
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Markus Blumberg, Karrar Al-Ameed, Erik Eiselt, Sandra Luber, Constantin Mamat, University of Zurich, and Mamat, Constantin
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10120 Department of Chemistry ,1602 Analytical Chemistry ,1601 Chemistry (miscellaneous) ,calixarenes ,barium ,chelation ,3002 Drug Discovery ,Organic Chemistry ,3003 Pharmaceutical Science ,Pharmaceutical Science ,Analytical Chemistry ,Chemistry (miscellaneous) ,1313 Molecular Medicine ,540 Chemistry ,Drug Discovery ,Molecular Medicine ,Physical and Theoretical Chemistry ,1606 Physical and Theoretical Chemistry ,1605 Organic Chemistry - Abstract
Two sets of functionalised calix[4]arenes, either with a 1,3-crown ether bridge or with an open-chain oligo ether moiety in 1,3-position were prepared and further equipped with additional deprotonisable sulfonamide groups to establish chelating systems for selected cations Sr2+, Ba2+, and Pb2+ ions. To improve the complexation behaviour towards these cations, calix[4]arenes with oligo ether groups and modified crowns of different sizes were synthesized. Association constants were determined by UV/Vis titration in acetonitrile using the respective perchlorate salts and logK values between 3.2 and 8.0 were obtained. These findings were supported by the calculation of the binding energies exemplarily for selected complexes with Ba2+.
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- 2022
48. Nanomaterials as Ultrasound Theragnostic Tools for Heart Disease Treatment/Diagnosis
- Author
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Edouard Alphandéry, University of Zurich, and Alphandéry, Edouard
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Heart Diseases ,10017 Institute of Anatomy ,QH301-705.5 ,1503 Catalysis ,Ultrasonic Therapy ,Contrast Media ,1607 Spectroscopy ,610 Medicine & health ,ultrasounds ,Theranostic Nanomedicine ,Catalysis ,Inorganic Chemistry ,1312 Molecular Biology ,1706 Computer Science Applications ,Humans ,cancer ,Physical and Theoretical Chemistry ,Biology (General) ,Molecular Biology ,nano-oncology ,QD1-999 ,Spectroscopy ,nanomaterials ,Ultrasonography ,Microbubbles ,nanotechnology ,1604 Inorganic Chemistry ,Organic Chemistry ,General Medicine ,nanomedicine ,Nanostructures ,Computer Science Applications ,Chemistry ,570 Life sciences ,biology ,1606 Physical and Theoretical Chemistry ,1605 Organic Chemistry - Abstract
A variety of different nanomaterials (NMs) such as microbubbles (MBs), nanobubbles (NBs), nanodroplets (NDs), and silica hollow meso-structures have been tested as ultrasound contrast agents for the detection of heart diseases. The inner part of these NMs is made gaseous to yield an ultrasound contrast, which arises from the difference in acoustic impedance between the interior and exterior of such a structure. Furthermore, to specifically achieve a contrast in the diseased heart region (DHR), NMs can be designed to target this region in essentially three different ways (i.e., passively when NMs are small enough to diffuse through the holes of the vessels supplying the DHR, actively by being associated with a ligand that recognizes a receptor of the DHR, or magnetically by applying a magnetic field orientated in the direction of the DHR on a NM responding to such stimulus). The localization and resolution of ultrasound imaging can be further improved by applying ultrasounds in the DHR, by increasing the ultrasound frequency, or by using harmonic, sub-harmonic, or super-resolution imaging. Local imaging can be achieved with other non-gaseous NMs of metallic composition (i.e., essentially made of Au) by using photoacoustic imaging, thus widening the range of NMs usable for cardiac applications. These contrast agents may also have a therapeutic efficacy by carrying/activating/releasing a heart disease drug, by triggering ultrasound targeted microbubble destruction or enhanced cavitation in the DHR, for example, resulting in thrombolysis or helping to prevent heart transplant rejection.
- Published
- 2022
49. Differential Expression of Serum Extracellular Vesicle miRNAs in Multiple Sclerosis: Disease-Stage Specificity and Relevance to Pathophysiology
- Author
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Nagiua Cuomo-Haymour, Giorgio Bergamini, Giancarlo Russo, Luka Kulic, Irene Knuesel, Roland Martin, André Huss, Hayrettin Tumani, Markus Otto, Christopher R. Pryce, University of Zurich, and Pryce, Christopher R
- Subjects
Adult ,Male ,Adolescent ,1503 Catalysis ,QH301-705.5 ,1607 Spectroscopy ,610 Medicine & health ,10071 Functional Genomics Center Zurich ,Catalysis ,Inorganic Chemistry ,Extracellular Vesicles ,Multiple Sclerosis, Relapsing-Remitting ,1312 Molecular Biology ,1706 Computer Science Applications ,Humans ,clinically isolated syndrome ,relapsing–remitting multiple sclerosis ,inflammation ,extracellular vesicles ,microRNA ,biomarker ,pathophysiology ,Physical and Theoretical Chemistry ,Biology (General) ,Molecular Biology ,QD1-999 ,Spectroscopy ,Aged ,1604 Inorganic Chemistry ,Gene Expression Profiling ,Organic Chemistry ,General Medicine ,Middle Aged ,10040 Clinic for Neurology ,Computer Science Applications ,Chemistry ,MicroRNAs ,Gene Expression Regulation ,10054 Clinic for Psychiatry, Psychotherapy, and Psychosomatics ,Female ,MicroRNA ,1606 Physical and Theoretical Chemistry ,Biomarkers ,1605 Organic Chemistry - Abstract
Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS). Its first clinical presentation (clinically isolated syndrome, CIS) is often followed by the development of relapsing–remitting MS (RRMS). The periphery-to-CNS transmission of inflammatory molecules is a major pathophysiological pathway in MS. This could include signalling via extracellular vesicle (EV) microRNAs (miRNAs). In this study, we investigated the serum EV miRNome in CIS and RRMS patients and matched controls, with the aims to identify MS stage-specific differentially expressed miRNAs and investigate their biomarker potential and pathophysiological relevance. miRNA sequencing was conducted on serum EVs from CIS-remission, RRMS-relapse, and viral inflammatory CNS disorder patients, as well as from healthy and hospitalized controls. Differential expression analysis was conducted, followed by predictive power and target-pathway analysis. A moderate number of dysregulated serum EV miRNAs were identified in CIS-remission and RRMS-relapse patients, especially relative to healthy controls. Some of these miRNAs were also differentially expressed between the two MS stages and had biomarker potential for patient-control and CIS–RRMS separations. For the mRNA targets of the RRMS-relapse-specific EV miRNAs, biological processes inherent to MS pathophysiology were identified using in silico analysis. Study findings demonstrate that specific serum EV miRNAs have MS stage-specific biomarker potential and contribute to the identification of potential targets for novel, efficacious therapies., International Journal of Molecular Sciences, 23 (3), ISSN:1422-0067
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- 2022
- Full Text
- View/download PDF
50. A MicroRNA Next-Generation-Sequencing Discovery Assay (miND) for Genome-Scale Analysis and Absolute Quantitation of Circulating MicroRNA Biomarkers
- Author
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Kseniya Khamina, Andreas B. Diendorfer, Susanna Skalicky, Moritz Weigl, Marianne Pultar, Teresa L. Krammer, Catharine Aquino Fournier, Amy L. Schofield, Carolin Otto, Aaron Thomas Smith, Nina Buchtele, Christian Schoergenhofer, Bernd Jilma, Bernhard J. H. Frank, Jochen G. Hofstaetter, Regina Grillari, Johannes Grillari, Klemens Ruprecht, Christopher E. Goldring, Hubert Rehrauer, Warren E. Glaab, Matthias Hackl, University of Zurich, and Hackl, Matthias
- Subjects
1503 Catalysis ,spike-in ,QH301-705.5 ,1607 Spectroscopy ,610 Medicine & health ,10071 Functional Genomics Center Zurich ,Catalysis ,Inorganic Chemistry ,Extracellular Vesicles ,1312 Molecular Biology ,1706 Computer Science Applications ,Humans ,10239 Institute of Laboratory Animal Science ,Circulating MicroRNA ,Biology (General) ,Physical and Theoretical Chemistry ,QD1-999 ,Molecular Biology ,Spectroscopy ,microRNA ,1604 Inorganic Chemistry ,Genome, Human ,Sequence Analysis, RNA ,next-generation sequencing ,small RNA-sequencing ,biomarkers ,toxicology ,drug safety ,Organic Chemistry ,High-Throughput Nucleotide Sequencing ,General Medicine ,Computer Science Applications ,Chemistry ,10036 Medical Clinic ,570 Life sciences ,biology ,590 Animals (Zoology) ,1606 Physical and Theoretical Chemistry ,Biomarkers ,1605 Organic Chemistry - Abstract
The plasma levels of tissue-specific microRNAs can be used as diagnostic, disease severity and prognostic biomarkers for chronic and acute diseases and drug-induced injury. Thereby, the combination of diverse microRNAs into biomarker signatures using multivariate statistics seems especially powerful from the perspective of tissue and condition specific microRNA shedding into the plasma. Although next-generation sequencing (NGS) technology enables one to analyse circulating microRNAs on a genome-scale level, it suffers from potential biases (e.g., adapter ligation bias) and lacks absolute transcript quantitation as well as tailor-made quality controls. In order to develop a robust NGS discovery assay for genome-scale quantitation of circulating microRNAs, we first evaluated the sensitivity, repeatability and ligation bias of four commercially available small RNA library preparation protocols. The protocol from RealSeq Biosciences was selected based on its performance and usability and coupled with a novel panel of exogenous small RNA spike-in controls to enable quality control and absolute quantitation, thus ensuring comparability of data across independent NGS experiments. The established microRNA Next-Generation-Sequencing Discovery Assay (miND) was validated for its relative accuracy, precision, analytical measurement range and sequencing bias and was considered fit-for-purpose for microRNA biomarker discovery. Summarized, all these criteria were met, and thus, our analytical platform is considered fit-for-purpose for microRNA biomarker discovery from biofluids in the setting of any diagnostic, prognostic or patient stratification need. The established miND assay was tested on serum, cerebrospinal fluid (CSF), synovial fluid (SF) and extracellular vesicles (EV) extracted from cell culture medium of primary cells and proved its potential to be used across different sample types.
- Published
- 2022
- Full Text
- View/download PDF
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