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  • 1.
    Allert, M
    et al.
    Univ Gothenburg, Dept Chem Organ Chem, S-41296 Gothenburg, Sweden Linkoping Univ, Dept Chem, S-58183 Linkoping, Sweden.
    Baltzer, Lars
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology.
    Setting the stage for new catalytic functions in designed proteins - Exploring the imine pathway in the efficient decarboxylation of oxaloacetate by an Arg-Lys site in a four-helix bundle protein scaffold2002In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 8, no 11, p. 2549-2560Article in journal (Refereed)
    Abstract [en]

    Fourteen 42-residue polypeptides have been designed to identify reactive sites for the catalysis of the decarboxylation of oxaloacetate, a chemical transformation that proceeds through the formation of an imine intermediate. The sequences fold into helix-loop-helix motifs and dimerise to four-helix bundles. The catalytically active lysine residues were incorporated in several surface exposed positions, but also in positions characterised by hydrophobic properties to reduce their pK(a) values. The molecular environments of the Lys residues were systematically varied, to find which residues were able to stabilise and bind the imine intermediate in the decarboxylation reaction. A two-residue Arg-Lys site formed the main component of the reactive site of the helix-loop-helix dimer Decarb-K34_R33, which obeyed saturation kinetics in catalysing the reaction with a k(cat)/K-M of 0.59m(-1) s(-1). The rate constant measured was nearly three orders of magnitude larger than the second-order rate constant of the butylamine-catalysed reaction (0.0011 M-1 s(-1)), and four orders of magnitude larger than the pseudo first-order rate constant of the uncatalysed reaction (1.3 x 10(-5) s(-1)). The sequence of Decarb-K34_R33 contained only a single lysine residue. It was flanked by an arginine in the preceding position in the sequence. A flanking Arg residue provided more efficient catalysis than a flanking Lys or Gln residue. Arginines in flanking positions in the helix, in positions four residues before or after the Lys in the sequence, are not as important in catalysis as the Arg of the Arg-Lys pair. The effect of pK(a) on the catalytic efficiency of the Lys residue in the decarboxylation reaction is well known. The identification of the role of the flanking Arg residue in catalysing decarboxylation, its optimal position, and the importance of conformational stability reported here sets the stage for developing a number of catalytic systems that depend on the formation of imine intermediates, but that lead to different reaction products.

  • 2.
    Anderson, LK
    et al.
    Univ Gothenburg, Dept Chem, S-41296 Gothenburg, Sweden Linkoping Univ, Dept Chem, S-58183 Linkoping, Sweden.
    Caspersson, M
    Univ Gothenburg, Dept Chem, S-41296 Gothenburg, Sweden Linkoping Univ, Dept Chem, S-58183 Linkoping, Sweden.
    Baltzer, Lars
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology.
    Control of lysine reactivity in four-helix bundle proteins by site-selective pK(a) depression: Expanding the versatility of proteins by postsynthetic functionalisation2002In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 8, no 16, p. 3687-3697Article in journal (Refereed)
    Abstract [en]

    Five 42-residue polypeptides have been designed to fold into hairpin helix-loop-helix motifs that dimerise to form four-helix bundles, and to serve as protein scaffolds for the elucidation at the molecular level of the principles that control and fine-tune lysine and ornithine reactivities in a protein context. Site-selective control of Lys and Orn reactivity provides a mechanism for addressing directly individual residues and is a prerequisite for the site-selective functionalisation of folded proteins. Several lysine and one ornithine residues were introduced on the surface and in the hydrophobic core of the folded motif. The reactivity of each residue was determined by measuring the degree of acylation of the trypsin cleaved fragments by HPLC and mass spectrometry. The most reactive residues were Orn34 and Lys19, both of which were located in d positions in the heptad repeat, and therefore in hydrophobic environments. Upon reaction of the helix-loop-helix dimer KA-I with one equivalent of mono-p-nitrophenyl fumarate, Orn34 was acylated approximately three times more efficiently than Lys19, whereas Lys10 (b position), Lys15 (g position), and Lys33 (c position) remained unmodified. In the sequence KA-I-A(15) Lys15 was replaced by an alanine residue and the selectivity of Orn34 over Lys19 increased to approximately a factor of six, probably because Lys15 had the capacity to reduce the pK(a) value of Lys19 and 85 % of site-selectively monoacylated product was obtained. The pH dependence of the acylation reaction was determined and showed that the pK(a) of the reactive residues were 9.3, more than a pK(a) unit below the magnitude of the corresponding residue in a solvent exposed position. Introducing Lys and Orn residues into a or d positions of the heptad repeat therefore serves as a mechanism of depressing their pKa to increase their reactivity site selectively. Extensive NMR and CD spectroscopic analyses showed that the sequences fold according to prediction.

  • 3.
    Bazzicalupi, Carla
    et al.
    University of Florence, Italy .
    Caltagirone, Claudia
    University of Cagliari, Italy .
    Cao, Zenfeng
    University of Roma Tor Vergata, Italy E China University of Science and Technology, Peoples R China .
    Chen, Qibin
    E China University of Science and Technology, Peoples R China .
    Di Natale, Corrado
    University of Roma Tor Vergata, Italy .
    Garau, Alessandra
    University of Cagliari, Italy .
    Lippolis, Vito
    University of Cagliari, Italy .
    Lvova, Larisa
    University of Roma Tor Vergata, Italy St Petersburg State University, Russia .
    Liu, Honglai
    E China University of Science and Technology, Peoples R China .
    Lundström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, The Institute of Technology.
    Mostallino, M. Cristina
    Ist Neurosci CNR Cagliari, Italy .
    Nieddu, Mattia
    University of Cagliari, Italy .
    Paolesse, Roberto
    University of Roma Tor Vergata, Italy .
    Prodi, Luca
    University of Bologna, Italy .
    Sgarzi, Massimo
    University of Bologna, Italy .
    Zaccheroni, Nelsi
    University of Bologna, Italy .
    Multimodal Use of New Coumarin-Based Fluorescent Chemosensors: Towards Highly Selective Optical Sensors for Hg2+ Probing2013In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 19, no 43, p. 14639-14653Article in journal (Refereed)
    Abstract [en]

    Despite several types of fluorescent sensing molecules have been proposed and examined to signal Hg2+ ion binding, the development of fluorescence-based devices for in-field Hg2+ detection and screening in environmental and industrial samples is still a challenging task. Herein, we report the synthesis and characterization of three new coumarin-based fluorescent chemosensors featuring mixed thia/aza macrocyclic framework as receptors units, that is, ligands L1-L3. These probes revealed an OFF-ON selective response to the presence of Hg2+ ions in MeCN/H2O 4:1 (v/v), which allowed imaging of this metal ion in Cos-7 cells in vitro. Once included in silica core-polyethylene glycol (PEG) shell nanoparticles or supported on polyvinyl chloride (PVC)-based polymeric membranes, ligands L1-L3 can also selectively sense Hg2+ ions in pure water. In particular we have developed an optical sensing array tacking advantage of the fluorescent properties of ligand L3 and based on the computer screen photo assisted technique (CSPT). In the device ligand L3 is dispersed into PVC membranes and it quantitatively responds to Hg2+ ions in natural water samples.

  • 4.
    Björk, Jonas
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Computational Physics. Linköping University, The Institute of Technology.
    Hanke, Felix
    Accelrys, 334 Science Park, Cambridge, CB4 0WN, United Kingdom.
    Towards Design Rules for Covalent Nanostructures on Metal Surfaces2014In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 20, no 4, p. 928-934Article in journal (Refereed)
    Abstract [en]

    The covalent molecular assembly on metal surfaces is explored, outlining the different types of applicable reactions. Density functional calculations for on-surface reactions are shown to yield valuable insights into specific reaction mechanisms and trends across the periodic table. Finally, it is shown how design rules could be derived for nanostructures on metal surfaces.

  • 5.
    Ding, Aixiang
    et al.
    Anhui University, Peoples R China.
    Yang, Longmei
    Anhui University, Peoples R China.
    Zhang, Yuyang
    Anhui University, Peoples R China.
    Zhang, Gaobin
    Anhui University, Peoples R China.
    Kong, Lin
    Anhui University, Peoples R China.
    Zhang, Xuanjun
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, The Institute of Technology.
    Tian, Yupeng
    Anhui University, Peoples R China; Shandong University, Peoples R China.
    Tao, Xutang
    Shandong University, Peoples R China.
    Yang, Jiaxiang
    Anhui University, Peoples R China; Shandong University, Peoples R China .
    Complex-Formation-Enhanced Fluorescence Quenching Effect for Efficient Detection of Picric Acid2014In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 20, no 38, p. 12215-12222Article in journal (Refereed)
    Abstract [en]

    Amine-functionalized alpha-cyanostilbene derivatives (Z)-2-(4-aminophenyl)-3-(4-butoxyphenyl) acrylonitrile (ABA) and (Z)-3-(4-butoxyphenyl)-2-[4-(butylamino) phenyl] acrylonitrile (BBA) were designed for specific recognition of picric acid (PA), an environmental and biological pollutant. The 1:1 host-guest complexes formed between the chemosensors and PA enhanced fluorescence quenching, thus leading to sensitive and selective detection in aqueous media and the solid phase.

  • 6.
    Durbeej, Bo
    et al.
    University of Sydney, Australia and Uppsala University, Sweden.
    Sandala, Gregory M
    University of Sydney, Australia.
    Bucher, Denis
    University of Sydney, Australia.
    Smith, David M.
    Rudjer Boskovic Institute, Zagreb, Croatia.
    Radom, Leo
    University of Sydney, Australia.
    On the importance of ribose orientation in the substrate activation of coenzyme B12-dependent mutases2009In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 15, no 34, p. 8578-8585Article in journal (Refereed)
    Abstract [en]

    The degree to which the corrin ring portion of coenzyme B12 can facilitate the H-atom-abstraction step in the glutamate mutase (GM)-catalyzed reaction of (S)-glutamate has been investigated with density functional theory. The crystal structure of GM identifies two possible orientations of the ribose portion of coenzyme B12. In one orientation (A), the OH groups of the ribose extend away from the corrin ring, whereas in the other orientation (B) the OH groups, especially that involving O3’, are instead directed towards the corrin ring. Our calculations identify a sizable stabilization amounting to about 30 kJ mol–1 in the transition structure (TS) complex corresponding to orientation B (TSBCorIm). In the TS complex where the ribose instead is positioned in orientation A, no such effect is manifested. The observed stabilization in TSBCorIm appears to be the result of favorable interactions involving O3’ and the corrin ring, including a C–H···O hydrogen bond. We find that the degree of stabilization is not particularly sensitive to the Co–C distance. Our calculations show that any potential stabilization afforded to the H-atom abstraction step by coenzyme B12 is sensitive to the orientation of the ribose moiety.

  • 7.
    Enander, Karin
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Dolphin, Gunnar
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Liedberg, Bo
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics. Linköping University, The Institute of Technology.
    Lundström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Applied Physics. Linköping University, The Institute of Technology.
    Baltzer, Lars
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    A versatile polypeptide platform for integrated recognition and reporting: affinity arrays for protein-ligand interaction analysis2004In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 10, no 10, p. 2375-2385Article in journal (Refereed)
    Abstract [en]

    A molecular platform for protein detection and quantification is reported in which recognition has been integrated with direct monitoring of target-protein binding. The platform is based on a versatile 42-residue helix–loop–helix polypeptide that dimerizes to form four-helix bundles and allows site-selective modification with recognition and reporter elements on the side chains of individually addressable lysine residues. The well-characterized interaction between the model target-protein carbonic anhydrase and its inhibitor benzenesulfonamide was used for a proof-of-concept demonstration. An affinity array was designed where benzenesulfonamide derivatives with aliphatic or oligoglycine spacers and a fluorescent dansyl reporter group were introduced into the scaffold. The affinities of the array members for human carbonic anhydrase II (HCAII) were determined by titration with the target protein and were found to be highly affected by the properties of the spacers (dissociation constant Kd=0.02–3 μM). The affinity of HCAII for acetazolamide (Kd=4 nM) was determined in a competition experiment with one of the benzenesulfonamide array members to address the possibility of screening substance libraries for new target-protein binders. Also, successful affinity discrimination between different carbonic anhydrase isozymes highlighted the possibility of performing future isoform-expression profiling. Our platform is predicted to become a flexible tool for a variety of biosensor and protein-microarray applications within biochemistry, diagnostics and pharmaceutical chemistry.

  • 8.
    Gatto, E.
    et al.
    Department of Chemical Sciences and Technologies, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, Italy.
    Malik, Muhammad Ali
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology.
    Di, Natale C.
    Di Natale, C., Department of Electronic Engineering, University of Rome Tor Vergata, Via del Politecnico 1, 00133 Rome, Italy.
    Paolesse, R.
    Department of Chemical Sciences and Technologies, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, Italy.
    D'Amico, A.
    Department of Electronic Engineering, University of Rome Tor Vergata, Via del Politecnico 1, 00133 Rome, Italy.
    Lundström, Ingemar
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Applied Physics .
    Filippini, Daniel
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Applied Physics .
    Polychromatic fingerprinting of excitation emission matrices2008In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 14, no 20, p. 6057-6060Article in journal (Refereed)
    Abstract [en]

    The ability of a ubiquitous polychromatic excitation to support the fingerprinting of the Excitation Emission Matrices (EEM) of fluorescent indicators was reported. Solutions of fluorescent molecules, with concentration of 2µM for the absorption and 10µM for the emission measurements were prepared. Spectroscopic grade THF and distilled water passed through Milli-Q purification system were used as solvents. EEM measurements were carried out on a spectrofluorimeter, operating in the 390-700 nm detection range, with excitations at 20 nm intervals within the same range. During the measurement, the screen displayed a sequence of 50 colors and for every color, the transmission and emission spectrum of both the reference and the sample were recorded. Illuminating colors in the red region are not able to excite fluorescence and this can be seen in the spectra for red light.

  • 9.
    Ge, Yi
    et al.
    Cranfield University, Bedfordshire, UK.
    Turner, Anthony P. F.
    Cranfield University, UK.
    Molecularly Imprinted Sorbent Assays: Recent Developments and Applications2009In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 15, no 33, p. 8100-8107Article, review/survey (Refereed)
    Abstract [en]

    Molecular imprinting has attracted considerable attention, because it offers the tantalising prospect of specific antibody-mimicking recognition and binding sites, coupled with several distinct advantages such as excellent stability, ease of preparation and low cost. In this Minireview, recent progress in molecularly imprinted sorbent assays is discussed, with a particular emphasis on the most significant developments and applications over the last few years.

  • 10.
    Hellwig, Raphael
    et al.
    Tech Univ Munich, Germany.
    Uphoff, Martin
    Tech Univ Munich, Germany.
    Paintner, Tobias
    Tech Univ Munich, Germany.
    Björk, Jonas
    Linköping University, Department of Physics, Chemistry and Biology, Thin Film Physics. Linköping University, Faculty of Science & Engineering.
    Ruben, Mario
    KIT, Sweden; Univ Strasbourg, France.
    Klappenberger, Florian
    Tech Univ Munich, Germany.
    Barth, Johannes V.
    Tech Univ Munich, Germany.
    Ho-Mediated Alkyne Reactions at Low Temperatures on Ag(111)2018In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 24, no 60, p. 16126-16135Article in journal (Refereed)
    Abstract [en]

    Low-temperature approaches to catalytic conversions promise efficiency, selectivity, and sustainable processes. Control over certain coupling reactions can be obtained via the pre-positioning of reactive moieties by self-assembly. However, in the striving field of on-surface synthesis atomistic precision and control remains largely elusive, because the employed coupling reactions proceed at temperatures beyond the thermal stability of the supramolecular templates. Here, utilizing scanning tunneling microscopy, we demonstrate terminal alkyne on-surface reactions mediated by Ho atoms at a weakly reactive Ag(111) substrate at lowtemperatures. Density functional theory calculations confirm the catalytic activity of the involved adatoms. Pre-deposited Ho induces alkyne dehydrogenation starting at substrate temperatures as low as 100 K. Ho arriving at molecularly pre-covered surfaces held at 130 and 200 K produces covalent enyne-linked dimers and initiates cyclotrimerization, respectively. Statistical product analysis indicates a two-step pathway for the latter, whereby the enyne intermediates influence the distribution of the products. High chemoselectivity results from the absence of cyclotetramerization and diyne-forming homocoupling. Our analysis indicates that mainly the arriving Ho adatoms enable the coupling. These findings support the concept of dynamic heterogeneity by single-atom catalysts and pave the way for alternative means to control on-surface reactions.

  • 11.
    Hu, Zhangjun
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Ahrén, Maria
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Selegård, Linnéa
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Skoglund, Caroline
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Söderlind, Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Engström, Maria
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences.
    Zhang, Xuanjun
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Uvdal, Kajsa
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Surface Physics and Nano Science. Linköping University, Faculty of Science & Engineering.
    Highly Water-Dispersible Surface-Modified Gd2O3 Nanoparticles for Potential Dual-Modal Bioimaging2013In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 19, no 38, p. 12658-12667Article in journal (Refereed)
    Abstract [en]

    Water-dispersible and luminescent gadolinium oxide (GO) nanoparticles (NPs) were designed and synthesized for potential dual-modal biological imaging. They were obtained by capping gadolinium oxide nanoparticles with a fluorescent glycol-based conjugated carboxylate (HL). The obtained nanoparticles (GO-L) show long-term colloidal stability and intense blue fluorescence. In addition, L can sensitize the luminescence of europium(III) through the so-called antenna effect. Thus, to extend the spectral ranges of emission, europium was introduced into L-modified gadolinium oxide nanoparticles. The obtained Eu-III-doped particles (Eu:GO-L) can provide visible red emission, which is more intensive than that without L capping. The average diameter of the monodisperse modified oxide cores is about 4nm. The average hydrodynamic diameter of the L-modified nanoparticles was estimated to be about 13nm. The nanoparticles show effective longitudinal water proton relaxivity. The relaxivity values obtained for GO-L and Eu:GO-L were r(1)=6.4 and 6.3s(-1)mM(-1) with r(2)/r(1) ratios close to unity at 1.4T. Longitudinal proton relaxivities of these nanoparticles are higher than those of positive contrast agents based on gadolinium complexes such as Gd-DOTA, which are commonly used for clinical magnetic resonance imaging. Moreover, these particles are suitable for cellular imaging and show good biocompatibility.

  • 12.
    Klingstedt, Therése
    et al.
    Linköping University, Faculty of Science & Engineering. Linköping University, Department of Physics, Chemistry and Biology, Chemistry.
    Shirani, Hamid
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Mahler, Jasmin
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Wegenast-Braun, Bettina M.
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Goedert, Michel
    MRC, England.
    Jucker, Mathias
    University of Tubingen, Germany; German Centre Neurodegenerat Disease, Germany.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Distinct Spacing Between Anionic Groups: An Essential Chemical Determinant for Achieving Thiophene-Based Ligands to Distinguish Beta-Amyloid or Tau Polymorphic Aggregates2015In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 21, no 25, p. 9072-9082Article in journal (Refereed)
    Abstract [en]

    The accumulation of protein aggregates is associated with many devastating neurodegenerative diseases and the existence of distinct aggregated morphotypes has been suggested to explain the heterogeneous phenotype reported for these diseases. Thus, the development of molecular probes able to distinguish such morphotypes is essential. We report an anionic tetrameric oligothiophene compound that can be utilized for spectral assignment of different morphotypes of -amyloid or tau aggregates present in transgenic mice at distinct ages. The ability of the ligand to spectrally distinguish between the aggregated morphotypes was reduced when the spacing between the anionic substituents along the conjugated thiophene backbone was altered, which verified that specific molecular interactions between the ligand and the protein aggregate are necessary to detect aggregate polymorphism. Our findings provide the structural and functional basis for the development of new fluorescent ligands that can distinguish between different morphotypes of protein aggregates.

  • 13.
    Klingstedt, Therése
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Shirani, Hamid
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Åslund, Andreas
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Cairns, Nigel J.
    Washington University, MO USA .
    Sigurdson, Christina J.
    University of Calif San Diego, CA USA .
    Goedert, Michel
    MRC, England .
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    The Structural Basis for Optimal Performance of Oligothiophene-Based Fluorescent Amyloid Ligands: Conformational Flexibility is Essential for Spectral Assignment of a Diversity of Protein Aggregates2013In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 19, no 31, p. 10179-10192Article in journal (Refereed)
    Abstract [en]

    Protein misfolding diseases are characterized by deposition of protein aggregates, and optical ligands for molecular characterization of these disease-associated structures are important for understanding their potential role in the pathogenesis of the disease. Luminescent conjugated oligothiophenes (LCOs) have proven useful for optical identification of a broader subset of disease-associated protein aggregates than conventional ligands, such as thioflavin T and Congo red. Herein, the molecular requirements for achieving LCOs able to detect nonthioflavinophilic Aβ aggregates or non-congophilic prion aggregates, as well as spectrally discriminate Aβ and tau aggregates, were investigated. An anionic pentameric LCO was subjected to chemical engineering by: 1) replacing thiophene units with selenophene or phenylene moieties, or 2) alternating the anionic substituents along the thiophene backbone. In addition, two asymmetric tetrameric ligands were generated. Overall, the results from this study identified conformational freedom and extended conjugation of the conjugated backbone as crucial determinants for obtaining superior thiophene-based optical ligands for sensitive detection and spectral assignment of disease-associated protein aggregates.

  • 14.
    Lin, Tao
    et al.
    Technical University of Munich, Germany.
    Zhang, Liding
    Technical University of Munich, Germany.
    Björk, Jonas
    Linköping University, Department of Physics, Chemistry and Biology, Theoretical Physics. Linköping University, Faculty of Science & Engineering.
    Chen, Zhi
    Karlsruhe Institute Technology, Germany.
    Ruben, Mario
    Karlsruhe Institute Technology, Germany; University of Strasbourg, France.
    Barth, Johannes V.
    Technical University of Munich, Germany.
    Klappenberger, Florian
    Technical University of Munich, Germany.
    Terminal Alkyne Coupling on a Corrugated Noble Metal Surface: From Controlled Precursor Alignment to Selective Reactions2017In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 23, no 62, p. 15588-15593Article in journal (Refereed)
    Abstract [en]

    Surface-templated covalent coupling of organic precursors currently emerges as a promising route to the atom-precise fabrication of low-dimensional carbon materials. Here, we investigate the adsorption and the coupling reactions of 4,4-diethynyl-1,1:4,1-terphenyl on Au(110) under ultra-high vacuum conditions by using scanning tunneling microscopy combined with density functional theory and kinetic Monte Carlo calculations. Temperature treatment induces both 1,2,4-asymmetric cyclotrimerization and homocoupling, resulting in various reaction products, including a previously unreported, surface-templated H-shaped pentamer. Our analysis of the temperature-dependent relative product abundances unravels that 1,2,4-trimerization and homocoupling proceed via identical intermediate species with the final products depending on the competition of coupling to a third monomer versus dehydrogenation. Our study sheds light on the control of coupling reactions by corrugated surfaces and annealing protocols.

  • 15.
    Matena, Manfred
    et al.
    University of Basel, Switzerland.
    Stöhr, Meike
    University of Basel, Switzerland.
    Riehm, Till
    University of Heidelberg, Germany.
    Björk, Jonas
    University of Liverpool, UK.
    Martens, Susanne
    University of Heidelberg, Germany.
    Dyer, Matthew S.
    University of Liverpool, UK.
    Persson, Mats
    University of Liverpool, UK.
    Lobo-Checa, Jorge
    University of Basel, Switzerland.
    Müller, Kathrin
    Paul-Scherrer-Institute, Villigen, Switzerland.
    Enache, Mihaela
    University of Basel, Switzerland.
    Wadepohl, Hubert
    University of Heidelberg, Germany.
    Zegenhagen, Jörg
    European Synchrotron Radiation Facility, Grenoble, France.
    Jung, Thomas A.
    Paul-Scherrer-Institute, Villigen, Switzerland.
    Gade, Lutz H.
    University of Heidelberg, Germany.
    Aggregation and contingent metal/surface reactivity of 1,3,8,10-tetraazaperopyrene (TAPP) on Cu(111)2010In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 16, no 7, p. 2079-2091Article in journal (Refereed)
    Abstract [en]

    The structural chemistry and reactivity of 1,3,8,10-tetraazaperopyrene (TAPP) on Cu(111) under ultra-high-vacuum (UHV) conditions has been studied by a combination of experimental techniques (scanning tunneling microscopy (STM) and X-ray photoelectron spectroscopy, XPS) and DFT calculations. Depending on the deposition conditions, TAPP forms three main assemblies, which result from initial submonolayer coverages based on different intermolecular interactions: a close-packed assembly similar to a projection of the bulk structure of TAPP, in which the molecules interact mainly through van der Waals (vDW) forces and weak hydrogen bonds; a porous copper surface coordination network; and covalently linked molecular chains. The Cu substrate is of crucial importance in determining the structures of the aggregates and available reaction channels on the surface, both in the formation of the porous network for which it provides the Cu atoms for surface metal coordination and in the covalent coupling of the TAPP molecules at elevated temperature. Apart from their role in the kinetics of surface transformations, the available metal adatoms may also profoundly influence the thermodynamics of transformations by coordination to the reaction product, as shown in this work for the case of the Cu-decorated covalent poly(TAPP-Cu) chains.

  • 16. Nilsson, J
    et al.
    Baltzer, Lars
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology.
    Reactive-site design in folded-polypeptide catalysts - The leaving group pK(a) of reactive esters sets the stage for cooperativity in nucleophilic and general-acid catalysis2000In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 6, no 12, p. 2214-2220Article in journal (Refereed)
    Abstract [en]

    The second-order rate constants for the hydrolysis of nitrophenyl esters catalysed by a number of folded designed polypeptides have been determined. and 1900-fold rate enhancements over those of the 4-methylimidazole-catalysed reactions have been observed. The rate enhancements are much larger than those expected from the pK(a) depression of the nucleophilic His residues alone. Kinetic solvent isotope effects were observed at pn values lower than the pK(a), values of the leaving groups and suggests that general-acid catalysis contributes in the pH range where the leaving group is predominantly protonated. In contrast, no isotope effects were observed at pH values above the pK(a) of the leaving group. A Hammett rho value of 1.4 has been determined fur the peptide-catalysed hydrolysis reaction by variation of the substituents of the leaving phenol. The corresponding values For the imidazole-catalysed reaction is 0.8 and For phenol dissociation is 2.2. There is therefore, very approximately, half a negative charge localised on the phenolate oxygen in the transition stair in agreement with the conclusion that transition-state hydrogen-bond formation may contribute to the observed catalysis. The elucidation at a molecular level of the principles that control cooperativity in the biocatalysed ester-hydrolysis reaction represents the first step towards a level of understanding of the concept of cooperativity that may eventually allow us to design tailor-made enzymes for chemical reactions not catalysed by nature.

  • 17.
    Pop, Flavia
    et al.
    University of Angers, France.
    Melan, Caroline
    University of Angers, France.
    Danila, Ion
    University of Angers, France.
    Linares, Mathieu
    Linköping University, Department of Physics, Chemistry and Biology, Theoretical Chemistry. Linköping University, The Institute of Technology.
    Beljonne, David
    University of Mons, Belgium.
    Amabilino, David B.
    Insitut Ciencia Mat Barcelona ICMAB CSIC, Spain.
    Avarvari, Narcis
    University of Angers, France.
    Hierarchical Self-Assembly of Supramolecular Helical Fibres from Amphiphilic C3-Symmetrical Functional Tris(tetrathiafulvalenes)2014In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 20, no 52, p. 17443-17453Article in journal (Refereed)
    Abstract [en]

    The preparation and self-assembly of the enantiomers of a series of C-3-symmetric compounds incorporating three tetrathiafulvalene (TTF) residues is reported. The chiral citronellyl and dihydrocitronellyl alkyl chains lead to helical one dimensional stacks in solution. Molecular mechanics and dynamics simulations combined with experimental and theoretical circular dichroism support the observed helicity in solution. These stacks self-assemble to give fibres that have morphologies that depend on the nature of the chiral alkyl group and the medium in which the compounds aggregate. An inversion of macroscopic helical morphology of the citronellyl compound is observed when compared to analogous 2-methylbutyl chains, which is presumably a result of the stereogenic centre being further away from the core of the molecule. This composition still allows both morphologies to be observed, whereas an achiral compound shows no helicity. The morphology of the fibres also depends on the flexibility at the chain ends of the amphiphilic components, as there is not such an apparently persistent helical morphology for the dihydrocitronellyl derivative as for that prepared from citronellyl chains.

  • 18.
    Rossi, P.
    et al.
    University of Padova, Department of Chemical Sciences, ITM-CNR Padova Section, Via Marzolo, 1, 35131 Padova, Italy.
    Tecilla, P.
    Dipartimento di Scienze Chimiche, Università di Trieste, Via Giorgieri 1, 34127 Trieste, Italy.
    Baltzer, Lars
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology.
    Scrimin, P.
    University of Padova, Department of Chemical Sciences, ITM-CNR Padova Section, Via Marzolo, 1, 35131 Padova, Italy.
    De novo metallonucleases based on helix-loop-helix motifs2004In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 10, no 17, p. 4163-4170Article in journal (Refereed)
    Abstract [en]

    Three new 42-mer peptides (PRI-III) designed to fold into a hairpin helix-loop-helix motif have been prepared. In the peptide sequence two (PRII-III) or four (PRI) copies of an unnatural amino acid bearing a triazacyclononane metal-ion binding site (ATANP) have been inserted in appropriate positions to allow the ligand subunits to face each other either within the same helix or between the two helices of the hairpin motif. Circular dichroism (C(d) studies in solution have shown that the apopeptides adopt a well-defined helix-loop-helix tertiary structure that dimerizes in solution at concentrations above 2001 µM to form a four-helix bundle. However, the helical content is strongly dependent on pH and metal-ion binding. Both protonation of the amines of the triazacyclononane units present in the ATANP lateral arm and complexation with ZnII ions cause a significant decrease of the helical content of the sequences. The ZnII complexes of the three peptides catalyze the transesterification of the RNA model substrate 2-hydroxypropyl-p-nitrophenyl phosphate (HPNP) with different efficiency. The best catalyst appears to be PRI-4ZnII. that is, the peptide incorporating four ATANP units. Michaelis-Menten saturation kinetics allowed us to estimate that substrate fully bound to the catalyst reacts 380 times faster than in its absence. The kinetic evidence suggests cooperativity between (at least two) metal ions: one activating the nucleophilic species (directly or indirectly) and the other facilitating nucleophilic attack by coordination of the phosphate.

  • 19.
    Rybakiewicz, Renata
    et al.
    Cardinal Stefan Wyszynski University, Poland; Warsaw University of Technology, Poland.
    Glowacki, Eric
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    Skorka, Lukasz
    Warsaw University of Technology, Poland.
    Pluczyk, Sandra
    Silesian Technical University, Poland.
    Zassowski, Pawel
    Silesian Technical University, Poland.
    Hazar Apaydin, Dogukan
    Johannes Kepler University of Linz, Austria.
    Lapkowski, Mieczyslaw
    Silesian Technical University, Poland; Polish Academic Science, Poland.
    Zagorska, Malgorzata
    Warsaw University of Technology, Poland.
    Pron, Adam
    Warsaw University of Technology, Poland.
    Low and High Molecular Mass Dithienopyrrole-Naphthalene Bisimide Donor-Acceptor Compounds: Synthesis, Electrochemical and Spectroelectrochemical Behaviour2017In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 23, no 12, p. 2839-2851Article in journal (Refereed)
    Abstract [en]

    Two low molecular weight electroactive donor-acceptor- donor (DAD)-type molecules are reported, namely naphthalene bisimide (NBI) symmetrically core-functionalized with dithienopyrrole (NBI-(DTP)(2)) and an asymmetric corefunctionalized naphthalene bisimide with dithienopyrrole (DTP) substituent on one side and 2-ethylhexylamine on the other side (NBI-DTP-NHEtHex). Both compounds are characterized by low optical bandgaps (1.52 and 1.65 eV, respectively). NBI-(DTP)(2) undergoes oxidative electropolymeriza-tion giving the electroactive polymer of ambipolar character. Its two-step reversible reduction and oxidation is corroborated by complementary EPR and UV/Vis-NIR spectroelectrochemical investigations. The polymer turned out to be electrochemically active not only in aprotic solvents but also in aqueous electrolytes, showing a distinct photocathodic current attributed to proton reduction. Additionally, poly(NBI-(DTP)(2)) was successfully tested as a photodiode material.

  • 20.
    Schubert, Vivien
    et al.
    Technical University of Berlin, Germany .
    Di Meo, Florent
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology. University of Limoges, France.
    Saaidi, Pierre-Loic
    Technical University of Berlin, Germany University of Evry Val dEssonne, France CNRS, France CEA, France .
    Bartoschek, Stefan
    Sanofi, Germany .
    Fiedler, Hans-Peter
    University of Tubingen, Germany .
    Trouillas, Patrick
    University of Limoges, France University of Mons UMONS, Belgium Palacky University, Czech Republic .
    Suessmuth, Roderich D.
    Technical University of Berlin, Germany .
    Stereochemistry and Conformation of Skyllamycin, a Non-Ribosomally Synthesized Peptide from Streptomyces sp Acta 28972014In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 20, no 17, p. 4948-4955Article in journal (Refereed)
    Abstract [en]

    Skyllamycin is a non-ribosomally synthesized cyclic depsipeptide from Streptomyces sp. Acta 2897 that inhibits PDGF-signaling. The peptide scaffold contains an N-terminal cinnamoyl moiety, a -methylation of aspartic acid, three -hydroxylated amino acids and one rarely occurring -hydroxy glycine. With the exception of -hydroxy glycine, the stereochemistry of the amino acids was assigned by comparison to synthetic reference amino acids applying chiral GC-MS and Marfey-HPLC analysis. The stereochemistry of -hydroxy glycine, which is unstable under basic and acidic conditions, was determined by conformational analysis, employing a combination of data from NOESY-NMR spectroscopy, simulated annealing and free MD simulations. The simulation procedures were applied for both R- and S-configured -hydroxy glycine of the skyllamycin structure and compared to the NOESY data. Both methods, simulated annealing and free MD simulations independently support S-configured -hydroxy glycine thus enabling the assignment of all stereocenters in the structure of skyllamycin and devising the role of two-component flavin dependent monooxygenase (Sky39) as S-selective.

  • 21.
    Shirani, Hamid
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Appelqvist, Hanna
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Bäck, Marcus
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Klingstedt, Therése
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Cairns, Nigel J.
    Washington University, MO USA.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Synthesis of Thiophene-Based Optical Ligands That Selectively Detect Tau Pathology in Alzheimers Disease2017In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 23, no 67, p. 17127-17135Article in journal (Refereed)
    Abstract [en]

    The accumulation of protein aggregates is associated with many devastating neurodegenerative diseases and the development of molecular ligands able to detect these pathological hallmarks is essential. Here, the synthesis of thiophene based optical ligands, denoted bi-thiophene-vinyl-benzothiazoles (bTVBTs) that can be utilized for selective assignment of tau aggregates in brain tissue with Alzheimers disease (AD) pathology is reported. The ability of the ligands to selectively distinguish tau deposits from the other AD associated pathological hallmark, senile plaques consisting of aggregated amyloid- (A) peptide, was reduced when the chemical composition of the ligands was altered, verifying that specific molecular interactions between the ligands and the aggregates are necessary for the selective detection of tau deposits. Our findings provide the structural and functional basis for the development of new fluorescent ligands that can distinguish between aggregated proteinaceous species consisting of different proteins. In addition, the bTVBT scaffold might be utilized to create powerful practical research tools for studying the underlying molecular events of tau aggregation and for creating novel agents for clinical imaging of tau pathology in AD.

  • 22.
    Shirani, Hamid
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Linares, Mathieu
    Linköping University, Department of Physics, Chemistry and Biology, Theoretical Chemistry. Linköping University, Faculty of Science & Engineering.
    Sigurdson, Christina J.
    University of Calif San Diego, CA 92093 USA.
    Lindgren, Mikael
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Norman, Patrick
    Linköping University, Department of Physics, Chemistry and Biology, Theoretical Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    A Palette of Fluorescent Thiophene-Based Ligands for the Identification of Protein Aggregates2015In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 21, no 43, p. 15133-15137Article in journal (Refereed)
    Abstract [en]

    By replacing the central thiophene unit of an anionic pentameric oligothiophene with other heterocyclic moities, a palette of pentameric thiophene-based ligands with distinct fluorescent properties were synthesized. All ligands displayed superior selectivity towards recombinant amyloid fibrils as well as disease-associated protein aggregates in tissue sections.

  • 23.
    Simon, Rozalyn
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Shirani, Hamid
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Åslund, K. O. Andreas
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Bäck, Marcus
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Haroutunian, Vahram
    Department of Psychiatry and Alzheimer’s Disease Research Center, Mount Sinai School of Medicine, New York, USA.
    Gandy, Sam
    Department of Psychiatry and Alzheimer’s Disease Research Center, Mount Sinai School of Medicine, New York, USA.
    Nilsson, Peter R
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Pentameric Thiophene-Based Ligands that Spectrally Discriminate Amyloid-b and Tau Aggregates Display Distinct Solvatochromism and Viscosity-Induced Spectral Shifts2014In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 20, no 39, p. 12537-12543Article in journal (Refereed)
    Abstract [en]

    A wide range of neurodegenerative diseases are characterized by the deposition of multiple protein aggregates. Ligands for molecular characterization and discrimination of these pathological hallmarks are thus important for understanding their potential role in pathogenesis as well as for clinical diagnosis of the disease. In this regard, luminescent conjugated oligothiophenes (LCOs) have proven useful for spectral discrimination of amyloid-beta (Aβ) and tau neurofibrillary tangles (NFTs), two of the pathological hallmarks associated with Alzheimer’s disease. Herein, the solvatochromism of a library of anionic pentameric thiophene-based ligands, as well as their ability to spectrally discriminate Aβ and tau aggregates, were investigated. Overall, the results from this study identified distinct solvatochromic and viscosity-dependent behavior of thiophene-based ligands that can be applied as indices to direct the chemical design of improved LCOs for spectral separation of Aβ and tau aggregates in brain tissue sections. The results also suggest that the observed spectral transitions of the ligands are due to their ability to conform by induced fit to specific microenvironments within the binding interface of each particular protein aggregate. We foresee that these findings might aid in the chemical design of thiophene-based ligands that are increasingly selective for distinct disease-associated protein aggregates.

  • 24.
    Torrens, Mabel
    et al.
    Universitat Rovira i Virgili, Tarragona, Spain.
    Ortiz, Mayreli
    Universitat Rovira i Virgili, Tarragona, Spain.
    Turner, Anthony P.F.
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, The Institute of Technology.
    Beni, Valerio
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, The Institute of Technology.
    O´Sullivan, Ciara K.
    Universitat Rovira i Virgili, Tarragona, Spain: ICREA, Barcelona, Spain.
    Controlled Zn-Mediated Grafting of Thin Layers of Bipodal Diazonium Salt on Gold and Carbon Substrates2014In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765Article in journal (Refereed)
    Abstract [en]

    A controlled, rapid, and potentiostat-free method has been developed for grafting the diazonium salt (3,5-bis(4-diazophenoxy)benzoic acid tetrafluoroborate (DCOOH)) on gold and carbon substrates, based on a Zn-mediated chemical dediazonation. The highly stable thin layer organic platforms obtained were characterized by cyclic voltammetry, AFM, impedance, XP, and Raman spectroscopies. A dediazonation mechanism based on radical formation is proposed. Finally, DCOOH was proved as a linker to an aminated electroactive probe.

  • 25.
    Zhang, Jun
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Sandberg, Alexander
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Konsmo, Audun
    Norwegian Univ Sci and Technol, Norway.
    Wu, Xiongyu
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    LeVine, Harry III
    Univ Kentucky, KY 40536 USA.
    Lindgren, Mikael
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering. Norwegian Univ Sci and Technol, Norway.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Detection and Imaging of A beta 1-42 and Tau Fibrils by Redesigned Fluorescent X-34 Analogues2018In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 24, no 28, p. 7210-7216Article in journal (Refereed)
    Abstract [en]

    We revisited the Congo red analogue 2,5-bis(4-hydroxy-3-carboxy-styryl)benzene (X-34) to develop this highly fluorescent amyloid dye for imaging Alzheimers disease (AD) pathology comprising A beta and Tau fibrils. A selection of ligands with distinct optical properties were synthesized by replacing the central benzene unit of X-34, with other heterocyclic moieties. Full photophysical characterization was performed, including recording absorbance and fluorescence spectra, Stokes shift, quantum yield and fluorescence lifetimes. All ligands displayed high affinity towards recombinant amyloid fibrils of A beta 1-42 (13-300nmK(d)) and Tau (16-200nmK(d)) as well as selectivity towards the corresponding disease-associated protein aggregates in AD tissue. We observed that these ligands efficiently displaced X-34, but not Pittsburgh compound B (PiB) from recombinant A beta 1-42 amyloid fibrils, arguing for retained targeting of the Congo red type binding site. We foresee that the X-34 scaffold offers the possibility to develop novel high-affinity ligands for A pathology found in human AD brain in a different mode compared with PiB, potentially recognizing different polymorphs of A fibrils.

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