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  • 1.
    Almstedt, Karin
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Amyloid fibrils of human prion protein are spun and woven from morphologically disordered aggregates2009In: Prion, ISSN 1933-6896, Vol. 3, no 4, p. 224-235Article in journal (Refereed)
    Abstract [en]

    Propagation and infectivity of prions in human prionopathies are likely associated with conversion of the mainly α-helical human prion protein, HuPrP, into an aggregated form with amyloid-like properties. Previous reports on efficient conversion of recombinant HuPrP have used mild to harsh denaturing conditions to generate amyloid fibrils in vitro. Herein we report on the in vitro conversion of four forms of truncated HuPrP (sequences 90-231 and 121-231 with and without an N-terminal hexa histidine tag) into amyloid-like fibrils within a few hours by using a protocol (phosphate buffered saline solutions at neutral pH with intense agitation) close to physiological conditions. The conversion process monitored by thioflavin T, ThT, revealed a three stage process with lag, growth and equilibrium phases. Seeding with preformed fibrils shortened the lag phase demonstrating the classic nucleated polymerization mechanism for the reaction. Interestingly, comparing thioflavin T kinetics with solubility and turbidity kinetics it was found that the protein initially formed non-thioflavionophilic, morphologically disordered aggregates that over time matured into amyloid fibrils. By transmission electron microscopy and by fluorescence microscopy of aggregates stained with luminescent conjugated polythiophenes (LCPs); we demonstrated that HuPrP undergoes a conformational conversion where spun and woven fibrils protruded from morphologically disordered aggregates. The initial aggregation functioned as a kinetic trap that decelerated nucleation into a fibrillation competent nucleus, but at the same time without aggregation there was no onset of amyloid fibril formation. The agitation, which was necessary for fibril formation to be induced, transiently exposes the protein to the air-water interface suggests a hitherto largely unexplored denaturing environment for prion conversion.

  • 2.
    Andersson, H.O.
    et al.
    Inst. of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.
    Fridborg, K.
    Inst. of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.
    Lowgren, S.
    Löwgren, S., Inst. of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.
    Alterman, M.
    Dept. of Organ. Pharmaceutical Chem., Uppsala University, Uppsala, Sweden.
    Muhlman, A.
    Mühlman, A., Department of Organic Chemistry, Stockholm University, Stockholm, Sweden.
    Bjorsne, M.
    Björsne, M., Department of Organic Chemistry, Stockholm University, Stockholm, Sweden.
    Garg, N.
    Dept. of Organ. Pharmaceutical Chem., Uppsala University, Uppsala, Sweden.
    Kvarnström, Ingemar
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Schaal, W.
    Dept. of Organ. Pharmaceutical Chem., Uppsala University, Uppsala, Sweden.
    Classon, B.
    Department of Organic Chemistry, Stockholm University, Stockholm, Sweden.
    Karlen, A.
    Karlén, A., Dept. of Organ. Pharmaceutical Chem., Uppsala University, Uppsala, Sweden.
    Danielsson, U.H.
    Department of Biochemistry, Uppsala University, Uppsala, Sweden.
    Ahlsen, G.
    Ahlsén, G., Department of Biochemistry, Uppsala University, Uppsala, Sweden.
    Nillroth, U.
    Department of Biochemistry, Uppsala University, Uppsala, Sweden.
    Vrang, L.
    Medivir AB, Lunastigen 7, Huddinge, Sweden.
    Oberg, B.
    Öberg, B., Medivir AB, Lunastigen 7, Huddinge, Sweden.
    Samuelsson, B.
    Department of Organic Chemistry, Stockholm University, Stockholm, Sweden.
    Hallberg, A.
    Dept. of Organ. Pharmaceutical Chem., Uppsala University, Uppsala, Sweden.
    Unge, T.
    Inst. of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden, Inst. of Cell and Molecular Biology, Box 590, Uppsala University, SE-751 24 Uppsala, Sweden.
    Optimization of P1-P3 groups in symmetric and asymmetric HIV-1 protease inhibitors2003In: European Journal of Biochemistry, ISSN 0014-2956, E-ISSN 1432-1033, Vol. 270, no 8, p. 1746-1758Article in journal (Refereed)
    Abstract [en]

    HIV-1 protease is an important target for treatment of AIDS, and efficient drugs have been developed. However, the resistance and negative side effects of the current drugs has necessitated the development of new compounds with different binding patterns. In this study, nine C-terminally duplicated HIV-1 protease inhibitors were cocrystallised with the enzyme, the crystal structures analysed at 1.8-2.3 Å resolution, and the inhibitory activity of the compounds characterized in order to evaluate the effects of the individual modifications. These compounds comprise two central hydroxy groups that mimic the geminal hydroxy groups of a cleavage-reaction intermediate. One of the hydroxy groups is located between the d-oxygen atoms of the two catalytic aspartic acid residues, and the other in the gauche position relative to the first. The asymmetric binding of the two central inhibitory hydroxyls induced a small deviation from exact C2 symmetry in the whole enzyme-inhibitor complex. The study shows that the protease molecule could accommodate its structure to different sizes of the P2/P2' groups. The structural alterations were, however, relatively conservative and limited. The binding capacity of the S3/S3' sites was exploited by elongation of the compounds with groups in the P3/P3' positions or by extension of the P1/P1' groups. Furthermore, water molecules were shown to be important binding links between the protease and the inhibitors. This study produced a number of inhibitors with Ki values in the 100 picomolar range.

  • 3.
    Andersson, Theresa
    et al.
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Lundqvist, Martin
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology . Linköping University, The Institute of Technology.
    Dolphin, Gunnar T.
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Enander, Karin
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics . Linköping University, The Institute of Technology.
    Jonsson, Bengt-Harald
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology . Linköping University, The Institute of Technology.
    Nilsson, Jonas W.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Baltzer, Lars
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    The binding of human Carbonic Anhydrase II by functionalized folded polypeptide receptors2005In: Chemistry and Biology, ISSN 1074-5521, E-ISSN 1879-1301, Vol. 12, no 11, p. 1245-1252Article in journal (Refereed)
    Abstract [en]

    Several receptors for human carbonic anhydrase II (HCAII) have been prepared by covalently attaching benzenesulfonamide carboxylates via aliphatic aminocarboxylic acid spacers of variable length to the side chain of a lysine residue in a designed 42 residue helix-loop-helix motif. The sulfonamide group binds to the active site zinc ion of human carbonic anhydrase II located in a 15 Å deep cleft. The dissociation constants of the receptor-HCAII complexes were found to be in the range from low micromolar to better than 20 nM, with the lowest affinities found for spacers with less than five methylene groups and the highest affinity found for the spacer with seven methylene groups. The results suggest that the binding is a cooperative event in which both the sulfonamide residue and the helix-loop-helix motif contribute to the overall affinity.

  • 4.
    Arja, Katriann
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology. Linköping, .
    Sjölander, Daniel
    Linköping University, Department of Physics, Chemistry and Biology, Protein Science. Linköping University, Faculty of Science & Engineering. Linköping, .
    Åslund, Alma
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, Faculty of Science & Engineering. Linköping, .
    Prokop, Stefan
    Charite, Germany .
    Heppner, Frank L.
    Charite, Germany .
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, Faculty of Science & Engineering. Linköping, .
    Lindgren, Mikael
    Norwegian University of Science and Technology, Norway .
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Protein Science. Linköping University, Faculty of Science & Engineering. Linköping, .
    Åslund, Andreas
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, Faculty of Science & Engineering. Linköping, .
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, Faculty of Science & Engineering. Linköping, .
    Enhanced Fluorescent Assignment of Protein Aggregates by an Oligothiophene-Porphyrin-Based Amyloid Ligand2013In: Macromolecular rapid communications, ISSN 1022-1336, E-ISSN 1521-3927, Vol. 34, no 9, p. 723-730Article in journal (Refereed)
    Abstract [en]

    Fluorescent probes identifying protein aggregates are of great interest, as deposition of aggregated proteins is associated with many devastating diseases. Here, we report that a fluorescent amyloid ligand composed of two distinct molecular moieties, an amyloidophilic pentameric oligothiophene and a porphyrin, can be utilized for spectral and lifetime imaging assessment of recombinant A 1-42 amyloid fibrils and A deposits in brain tissue sections from a transgenic mouse model with Alzheimers disease pathology. The enhanced spectral range and distinct lifetime diversity of this novel oligothiopheneporphyrin-based ligand allow a more precise assessment of heterogeneous amyloid morphology compared with the corresponding oligothiophene dye.

  • 5.
    Aslund, Andreas
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Fluorescent oligo and poly-thiophenes and their utilization for recording biological events of diverse origin-when organic chemistry meets biology.2009In: Journal of chemical biology, ISSN 1864-6166, Vol. 2, no 4, p. 161-175Article in journal (Refereed)
    Abstract [en]

    The technique of using luminescent oligo-thiophenes and luminescent conjugated poly-thiophenes to monitor biological processes has gained increased interest from scientists within different research areas, ranging from organic chemistry and photo-physics to biology since its introduction. The technique is generally straightforward and requires only standard equipment, and the result is available within minutes from sample preparation. In this review, the syntheses of oligo and polythiophenes developed over the last decades are discussed. Furthermore, the utilization of these molecular agents for exploring biological events, e.g., DNA hybridization or protein misfolding events, are covered.

  • 6.
    Baltzer, Lars
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology.
    Nilsson, Helena
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Nilsson, Jonas
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    De novo design of proteins - What are the rules?2001In: Chemical Reviews, ISSN 0009-2665, E-ISSN 1520-6890, Vol. 101, no 10, p. 3153-3163Article, review/survey (Refereed)
    Abstract [en]

    The different techniques used for analyzing protein folding were discussed. The design of polypeptides that fold into structures that are preorganized to form specific protein-protein interactions was also discussed. The construction of cavities was found to be a necessary step in the design of efficient catalysts and selective receptors.

  • 7.
    Baltzer, Lars
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology.
    Nilsson, Jonas
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Emerging principles of de novo catalyst design2001In: Current Opinion in Biotechnology, ISSN 0958-1669, E-ISSN 1879-0429, Vol. 12, no 4, p. 355-360Article, review/survey (Refereed)
    Abstract [en]

    Considerable progress has been made in the understanding of how to exploit hydrophobic and charge - charge interactions in forming binding sites for peptides and small molecules in folded polypeptide catalysts. This knowledge has enabled the introduction of feedback and control functions into catalytic cycles and the construction of folded polypeptide catalysts that follow saturation kinetics. Major advances have also been made in the design of metalloproteins and metallopeptides, especially with regards to understanding redox potential control.

  • 8.
    Benesch, Johan
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology.
    Svedhem, S.
    Svensson, Stefan
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Valiokas, Ramunas
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology.
    Liedberg, Bo
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics .
    Tengvall, Pentti
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Applied Physics .
    Protein adsorption to oligo(ethylene glycol) self-assembled monolayers: Experiments with fibrinogen, heparinized plasma, and serum2001In: Journal of Biomaterials Science. Polymer Edition, ISSN 0920-5063, E-ISSN 1568-5624, Vol. 12, no 6, p. 581-597Article in journal (Refereed)
    Abstract [en]

    Low protein adsorption is believed advantageous for blood-contacting materials and ethylene glycols (EG)-based polymeric compounds are often attached to surfaces for this purpose. In the present study, the adsorption of fibrinogen, serum, and plasma were studied by ellipsometry on a series of well-defined oligo(EG) terminated alkane-thiols self-assembled on gold. The layers were prepared with compounds of the general structure HS-(CH2)15-CONH-EGn, where n = 2, 4, and 6. Methoxy-terminated tri(EG) undecanethiol and hydroxyl-terminated hexadecanethiol self-assembled monolayers (SAMs) were used as references. The results clearly demonstrate that the adsorption depends on the experimental conditions with small amounts of fibrinogen adsorbing from a single protein solution, but larger amounts of proteins from serum and plasma. The adsorption of fibrinogen and blood plasma decreased with an increasing number of EG repeats and was temperature-dependent. Significantly less serum adsorbed to methoxy tri(EG) than to hexa(EG) and more proteins remained on the latter surface after incubation in a sodium dodecyl sulfate (SDS) solution, indicating a looser protein binding to the methoxy-terminated surface. All surfaces adsorbed complement factor 3(C3) from serum and plasma, although no surface-mediated complement activation was observed. The present study points to the importance of a careful choice of the protein model system before general statements regarding the protein repellant properties of potential surfaces can be made.

  • 9.
    Berg, Ina
    et al.
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Curcumin alleviates Aβ indcuced neurotoxicity and vice versa without removing amyloid deposits in transgenic DrosophilaManuscript (preprint) (Other academic)
    Abstract [en]

    Curcumin has been proposed to facilitate clearance of toxic amyloid formed by the Aβ peptide. To further address this notion, different concentrations of curcumin were tried for its effects in various Drosophila Alzheimer’s disease (AD) models. This study entailed five different Drosophila AD models (four Aβ expressing lines, and one tau expressing line), expressing the AD associated proteins using the Gal4/UAS system. These were assayed for several aspects of neurological impairment, including survival, climbing behavior, as well as locomotor activity. In addition, amyloid deposition was assessed by histological analysis. Curcumin treatment substantially prolonged the lifespan and improved climbing and locomotor activity for flies with severe disease geneotypes (Aβ1-42 E22G and double expressing Aβ1-42). In comparison, curcumin feeding of control flies resulted in a concentration-dependent shortened lifespan, whereas no such toxic side effects were found for AD genotypes with a mild phenotype (single expressors of Aβ1-40 and Aβ1-42). All flies expressing Aβ and tau displayed a higher total locomotor activity, and a continuation of the activity over a larger number of hours upon curcumin treatment. Unexpectedly, no change in tissue amyloid deposition upon curcumin treatment was observed. In vitro fibrillation of Aβ1-42, followed by Western blot and transmission electron microscopy in the presence and absence of curcumin, displayed enhanced fibrillation into large aggregates and decreased population of oligomers in curcumin samples. The decrease in oligomer formation by curcumin may explain why it increases the lifespan and activity without removing of the amyloid deposits seen in tissues. We also suggest that Aβ, at least in the context of Drosophila, functions as a chemical detoxifier sequestering curcumin and thereby mitigating its toxicity.

  • 10.
    Berg, Ina
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Efficient imaging of amyloid deposits in Drosophila models of human amyloidoses2010In: Nature Protocols, ISSN 1754-2189, E-ISSN 1750-2799, Vol. 5, no 5, p. 935-944Article in journal (Refereed)
    Abstract [en]

    Drosophila melanogaster is emerging as an important model system for neurodegenerative disease research. In this protocol, we describe an efficient method for imaging amyloid deposits in the Drosophila brain, by the use of a luminescent-conjugated oligothiophene (lco), p-Ftaa polymer probe. We also demonstrate the feasibility of co-staining with antibodies and compare the lco staining with standard amyloid-specific probes. the lco protocol enables high-resolution imaging of several different protein aggregates, such as aβ1-42, aβ1-42e22G, transthyretin V30M and human tau, in the Drosophila brain. aβ and tau aggregates could also be distinguished from each other because of distinct lco emission spectra. Furthermore, this protocol enables threedimensional brain mapping of amyloid distribution in whole-mount Drosophila brains. the use of p-Ftaa combined with other probes, antibodies and/or dyes will aid the rapid characterization of various amyloid deposits in the rapidly growing number of Drosophila models of neurodegenerative diseases.

  • 11.
    Bett, Cyrus
    et al.
    University of Calif San Diego, USA .
    Fernandez-Borges, Natalia
    Centre Cooperat Research Biosci CIC bioGUNE, Spain .
    Kurt, Timothy D.
    University of Calif San Diego, USA .
    Lucero, Melanie
    University of Calif San Diego, USA .
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Castilla, Joaquin
    Centre Cooperat Research Biosci CIC bioGUNE, Spain Basque Fdn Science IkerBasque, Spain .
    Sigurdson, Christina J.
    University of Calif San Diego, USA.
    Structure of the beta 2-alpha 2 loop and interspecies prion transmission2012In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 26, no 7, p. 2868-2876Article in journal (Refereed)
    Abstract [en]

    Prions are misfolded, aggregated conformers of the prion protein that can be transmitted between species. The precise determinants of interspecies transmission remain unclear, although structural similarity between the infectious prion and host prion protein is required for efficient conversion to the misfolded conformer. The beta 2-alpha 2 loop region of endogenous prion protein, PrPC, has been implicated in barriers to prion transmission. We recently discovered that conversion was efficient when incoming and host prion proteins had similar beta 2-alpha 2 loop structures; however, the roles of primary vs. secondary structural homology could not be distinguished. Here we uncouple the effect of primary and secondary structural homology of the beta 2-alpha 2 loop on prion conversion. We inoculated prions from animals having a disordered or an ordered beta 2-alpha 2 loop into mice having a disordered loop or an ordered loop due to a single residue substitution (D167S). We found that prion conversion was driven by a homologous primary structure and occurred independently of a homologous secondary structure. Similarly, cell-free conversion using PrPC from mice with disordered or ordered loops and prions from 5 species correlated with primary but not secondary structural homology of the loop. Thus, our findings support a model in which efficient interspecies prion conversion is determined by small stretches of the primary sequence rather than the secondary structure of PrP.

  • 12.
    Björefors, Fredrik
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics .
    Ekeroth, Johan
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology.
    Borgh, Annika
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics .
    Liedberg, Bo
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics .
    Lundström, Ingemar
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Applied Physics .
    Konradsson, Peter
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Electrochemical Analysis of Self-Assembled Monolayers2001In: Analysdagarna,2001, 2001Conference paper (Refereed)
  • 13.
    Björk, Per
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Lenner, Liselotte
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Kågedal, Bertil
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences.
    Persson, Birgitta
    Linköping University, Department of Biomedicine and Surgery. Linköping University, Faculty of Health Sciences.
    Inganäs, Olle
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Jonasson, Jon
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Conjugated polythiophene probes target lysosome-related acidic vacuoles in cultured primary cells2007In: Molecular and Cellular Probes, ISSN 0890-8508, Vol. 21, no 5-6, p. 329-337Article in journal (Refereed)
    Abstract [en]

    Conformation-sensitive optical probes for studying biological processes and structures are of great interest. The present work shows for the first time that conjugated polyelectrolyte (CPE) probes can be used for specific targeting of chromatin, nuclear and cytoplasmatic vesicles, and cytoskeletal components in a complex system of cultured cells. One of the probes could also be used for vital staining of live cells. When bound to different entities, the polythiophene derivative probes emitted light with different colors due to the unique spectral properties of these conformation sensitive probes. The physical pre-requisites for binding could also be exploited for characterization of the target. Unexpectedly, lysosome-related acidic vacuoles were targeted in cultured primary cells by both anionic, cationic, and zwitter-ionic polythiophene derivatives. Pre-treatment with Bafilomycin A1, a specific inhibitor of vacuolar-type H+-ATPase, caused redistribution of the staining. The targeting of lysosome-related acidic vesicles could not be demonstrated in transformed cells (melanoma, neuroblastoma, and prostate cancer cell lines), indicating a difference in the localization, structure, accessibility, or quantity of the target in cultured normal cells as compared with the malignant cell lines. The chemical nature of the conjugated polyelectrolyte complex in the cytoplasmatic vacuoles remains elusive.

  • 14. Blomberg, Eva
    et al.
    Claesson, Per M.
    Konradsson, Peter
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Liedberg, Bo
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics .
    Globotriose- and oligo(ethylene glycol)-terminated self-assembled monolayers: Surface forces, wetting, and surfactant adsorption2006In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 22, no 24, p. 10038-10046Article in journal (Refereed)
    Abstract [en]

    A set of oligo( ethylene glycol)-terminated and globotriose-terminated self-assembled monolayers (SAMs) has been prepared on gold substrates. Such model surfaces are well defined and have good stability due to the strong binding of thiols and disulfides to the gold substrate. They are thus very suitable for addressing questions related to effects of surface composition on wetting properties, surface interactions, and surfactant adsorption. These issues are addressed in this report. Accurate wetting tension measurements have been performed as a function of temperature using the Wilhelmy plate technique. The results show that the nonpolar character of oligo( ethylene glycol)-terminated SAMs increases slightly but significantly with temperature in the range 20-55 degrees C. On the other hand, globotriose-terminated SAMs are fully wetted by water at room temperature. Surface forces measurements have been performed and demonstrated that the interactions between oligo( ethylene glycol)-terminated SAMs are purely repulsive and similar to those determined between adsorbed surfactant layers with the same terminal headgroup. On the other hand, the interactions between globotriose-terminated SAMs include a short-range attractive force component that is strongly affected by the packing density in the layer. In some cases it is found that the attractive force component increases with contact time. Both these observations are rationalized by an orientation- and conformation-dependent interaction between globotriose headgroups, and it is suggested that hydrogen-bond formation, directly or via bridging water molecules, is the molecular origin of these effects.

  • 15.
    Borgh, Annika
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics . Linköping University, The Institute of Technology.
    Ekeroth, Johan
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Petoral Jr., Rodrigo M.
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics . Linköping University, The Institute of Technology.
    Uvdal, Kajsa
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics . Linköping University, The Institute of Technology.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic 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.
    A new route to the formation of biomimetic phosphate assemblies on gold: Synthesis and characterization2006In: Journal of Colloid and Interface Science, ISSN 1095-7103, Vol. 295, no 1, p. 41-49Article in journal (Refereed)
    Abstract [en]

    A biomimetic model system based on long-chain alkanethiols tailored with serine, threonine and tyrosine side-chain groups is created as a platform for the study of phosphorylated amino acids. The phosphorylated analogues are synthesized with protective tert-butyl groups that after assembly on thin polycrystalline gold films are removed in an acidic deprotection solution to form the corresponding phosphate self-assembled monolayers (SAMs). The SAMs are thoroughly characterized with null ellipsometry, contact angle goniometry, infrared reflection–absorption spectroscopy and X-ray photoelectron spectroscopy. The assembly and the subsequent deprotection process are optimized with respect to molecular orientation and chain conformation by varying the incubation time and the exposure time to the deprotection solution. The high quality of the generated SAMs suggests that the present assembly/deprotection approach is an attractive alternative when traditional synthetic routes become demanding because of solubility problems.

  • 16.
    Bui, Lan
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Synthesis of Substituted Alkanethiols Intended forProtein Immobilization: Chelate Associated Photochemistry (CAP)2009Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    The first and main part of this thesis is focused on the design and synthesis of photo-activableand metal chelating alkanethiols. Chelate associated photochemistry (CAP) is a novel conceptof combining two well-known protein (ligand) immobilization strategies to obtain a sensorsurface of covalently bound ligand with defined orientation. This includes nitrilotriacetic acid(NTA) which is used to capture and pre-orientate histidine-tagged proteins to the sensorsurface, followed by UV activation of a neighboring photo-crosslinking agent, benzophenone(BP), to covalently bind the ligand in this favorable orientation. Our results (paper 1) indicatethat up to 55% more activity of the ligand is achieved with the CAP concept compared to theactivity of the randomly oriented ligand (immobilized only by BP). This also yields a surfacethat is more robust compared to if only NTA is used. The photo cross-linking withbenzophenone (BP) adduct is limited to a distance range of 3Å, it is therefore favorable tocapture the ligand before reacting with surface bound BP-adduct. The surface consists of anexcess of ethylene glycols (known for its protein-repellent properties) to prevent non-specificprotein binding, thereby increase the specificity of the sensor surface. With this obtainedsurface chemistry we hope to contribute to the development of large-scale screening systemsand microarrays based on His-tagged labeled biomolecules. This will be used in a number ofapplications such as proteomics-related applications, including drug discovery, the discoveryof lead compounds and characterization of protein-protein interactions.

    The second part of this thesis describes the effect of the synthetic N-(3-oxododecanoyl)-Lhomoserinelactone (30-C12-HSL) on eukaryotic cells. 30-C12-HSL is a natural occurringsignal substance in the bacterium Pseudomonas aeruginosa, and this signal molecule isinvolved in the regulation of bacterial growth. Pseudomonas aeruginosa has been consideredas a common cause of infections in hospitals, especially in patients with compromisedimmune systems. Since the 30-C12-HSL can diffuse freely cross the cell membranes, it isexpected to have influence on the host cell behaviour. Herein, we study how the eukaryoticcells respond to the bacterial signal molecule, 30-C12-HSL. Our results (paper 2) indicatethat 30-C12-HSL disrupt the adherens junctions in human epithelial cells. The disruption iscaused by a hyperphosphorylation of the adherens junction proteins (protein complexbetween epithelial tissues). This suggests the bacterial signals are sensed by that the host cells.

    List of papers
    1. Oriented Protein Immobilization by Chelate Associated Photochemistry
    Open this publication in new window or tab >>Oriented Protein Immobilization by Chelate Associated Photochemistry
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    We demonstrate herein the synthesis, characterization and application of a novel chelateassociated photochemistry (CAP) for oriented and robust attachment of biomolecular ligandsto sensing surfaces. The chelation agent is nitrilotriacetic acid (NTA) which is capable ofcoordinating two histidine (His) molecules in the presence of Nickel. Therefore a ligandmodified with a His-sequence can be attached to NTA to form an oriented assembly ofligands on the sensor surface. The ligand is then covalently bound to the surface via a nearbyphotolabile benzophenone (BP) which attacks C-H bonds upon UV light activation. Theligand is then available for analyte interaction. The synthesized compounds used in this studyare based on the well-known organosulphur surface chemistry for proper attachment to goldsurfaces. Besides the two BP and NTA alkane thiols/disulphides we also synthesized a fillermolecule with an oligo (ethylene glycol) (OEG) tail to fine tune the surface composition andto reduce non-specific binding. Results from surface plasmon resonance (SPR) measurementsusing a Biacore 3000 instrument indicate that up to 55% larger analyte response is obtainedwith CAP as compared to the response obtained with the random orientation achieved byphotoimmobilization alone.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-20647 (URN)
    Available from: 2009-09-16 Created: 2009-09-16 Last updated: 2013-01-30
    2. The junctional integrity of epithelial cells is modulated by Pseudomonas aeruginosa quorum sensing molecule through phosphorylation-dependent mechanisms
    Open this publication in new window or tab >>The junctional integrity of epithelial cells is modulated by Pseudomonas aeruginosa quorum sensing molecule through phosphorylation-dependent mechanisms
    2009 (English)In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 315, no 2, p. 313-326Article in journal (Refereed) Published
    Abstract [en]

    In Pseudomonas aeruginosa, cell-cell Communication based on acyl-homoserine lactone (HSL) quorum sensing molecules is known to coordinate the production of virulence factors and biofilms by the bacterium. Incidentally, these bacterial signals can also modulate mammalian cell behaviour. We report that 3O-C-12-HSL can disrupt adherens junctions in human epithelial Caco-2 cells as evidenced by a reduction of the expression and distribution of E-cadherin and beta-catenin. Using co-immunoprecipitation we also found that P. aeruginosa 3O-C-12-HSL-treatment resulted in tyrosine hyperphosphorylation of E-cadherin, beta-catenin, occludin and ZO-1. Similarly, serine and threonine residues of E-cadherin and ZO-1 became more phosphorylated after 3O-C-12-HSL treatment. On the contrary, occludin and beta-catenin underwent dephosphorylation on serine and threonine residues after exposition of 3O-C-12-HSL. These changes in the phosphorylation state were paralleled by alteration in the Structure of junction complexes and increased paracellular permeability. Moreover, pre-treatment of the Caco-2 cells with protein phosphatase and kinase inhibitors prevented 3O-C-12-HSL-induced changes in paracellular permeability and interactions between occludin-ZO-1 and the E-cadherin-beta-catenin. These findings clearly suggest that an alteration in the phosphorylation status of junction proteins are involved in the changes in cell junction associations and enhanced paracellular permeability, and that bacterial signals are indeed sensed by the host cells.

    Keywords
    Quorum sensing, Pseudomonas aeruginosa, Acyl-homoserine lactone, Epithelial barrier, Adherens and tight junctions, Protein phosphorylations/dephosphorylations
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-16627 (URN)10.1016/j.yexcr.2008.10.044 (DOI)
    Available from: 2009-02-08 Created: 2009-02-06 Last updated: 2017-12-14Bibliographically approved
  • 17.
    Buskas, T
    et al.
    Univ Stockholm, Arrhenius Lab, Dept Organ Chem, S-10691 Stockholm, Sweden Linkoping Univ, Dept Chem, S-58183 Linkoping, Sweden.
    Konradsson, Peter
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Synthesis of oligosaccharides designed to form micelles, corresponding to structures found in ovarian cyst fluid2000In: Journal of carbohydrate chemistry, ISSN 0732-8303, E-ISSN 1532-2327, Vol. 19, no 1, p. 25-51Article in journal (Refereed)
    Abstract [en]

    The syntheses of alpha-D-GlcpNAc-(1-->4)-beta-D-Galp-(1-->4)-beta-D-GlcNAc-(1-->O)-(CH2)(15)CH3 (1) and fragments thereof, corresponding to structures found in human ovarian cyst fluid, are described. Silver triflate promoted coupling of 3.4,6-tri-O-acetyl-2-azido-2-deoxy-beta-D-glucopyranosyl bromide (12) and galactose acceptor (11) gave a disaccharide donor (13), which was readily transformed into the corresponding bromo-derivative 18. For the synthesis of disaccharide beta-D-Galp-(1-->4)-D-GlcNAc, several differently protected glucosamine accepters were prepared. It was found that cetyl alcohol needed to be introduced after the formation of the P-galactoside bond. Glycosylation of pent-4-enyl 3,6-di-O-benzyl-2-deoxy-2-tetrachlorophthalimido-beta-D-glucopyranoside (30) with (3,4,6-tri-O-acetyl-2-azido-2-deoxy-alpha-D-glucopyranosyl)-(1-->4)-2,3,6-tri-O-benzoyl-alpha-D-galactopyranosyl bromide (18) by use of silver triflate as promoter gave the desired trisaccharide 31. Finally 31 was transformed via coupling to the long alkyl chain aglycon and deprotection into the title compound 1.

  • 18.
    Buskas, T.
    et al.
    Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden.
    Konradsson, Peter
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Oscarson, S.
    Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden.
    Efficient synthesis of polylactosamine structures through regioselective glycosylations2001In: Journal of carbohydrate chemistry, ISSN 0732-8303, E-ISSN 1532-2327, Vol. 20, no 7-8, p. 569-583Article in journal (Refereed)
    Abstract [en]

    Di-, tri-and tetramers of ß-(1?3)-linked N-acetyllactosamine residues have been synthesised as their methyl glycosides, to be used in ITC binding studies to various galectins. The synthetic strategy involves two types of regioselective glycosylations: couplings of a galactosyl donor to 3,4-diol N-tetrachlorophthalimido glucose acceptors to give the lactosamine monomer building blocks, and subsequent formation of the oligomers through consecutive couplings of lactosamine donors to 2',3',4'-lactosamine acceptors, with high selectivity for the desired products.

  • 19.
    Buskas, T.
    et al.
    Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden.
    Soderberg, E.
    Söderberg, E., Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden.
    Konradsson, Peter
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Fraser-Reid, B.
    NPG Research Institute, 710 West Main Street, Durham, NC 27701, United States.
    Use of n-pentenyl glycosides as precursors to various spacer functionalities2000In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 65, no 4, p. 958-963Article in journal (Refereed)
    Abstract [en]

    Pent-4-enyl ß-D-glucopyranoside and its peracetylated and perbenzylated derivatives are shown to be excellent substrates for preparation of a wide variety of spacer functionalities. The spacer derivatives so obtained are promising substrates for preparing agents such as neo-glycoconjugates, micelies, and liquid crystalline phases, which are of interest for studying various biological and physiological phenomena of carbohydrates.

  • 20.
    Bäck, Marcus
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Design and Synthesis of Hepatitis C Virus NS3 Protease Inhibitors Incorporating a P2 Cyclopentane-Derived Scaffold2006Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis describes the design, synthesis and structure-activity relationships analysis of potential inhibitors targeting the hepatitis C virus (HCV) NS3 protease. Also discussed is the disease caused by HCV infection and the class of enzymes known as proteases. Furthermore are explained why such enzymes can be considered to be suitable targets for developing drugs to combat diseases in general and in particular HCV, focusing on the NS3 protease. Moreover, some strategies used to design protease inhibitors and the desired properties of potential drug candidates are briefly examined. Synthesis of linear and macrocyclic NS3 protease inhibitors comprising a designed trisubstituted cyclopentane moiety as an N-acyl-(4R)-hydroxyproline bioisostere is also addressed, and several very potent and promising compounds are evaluated.

    List of papers
    1. Potent inhibitors of the hepatitis C virus NS3 protease: use of a novel P2 cyclopentane-derived template
    Open this publication in new window or tab >>Potent inhibitors of the hepatitis C virus NS3 protease: use of a novel P2 cyclopentane-derived template
    Show others...
    2006 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 14, no 15, p. 5136-5151Article in journal (Refereed) Published
    Abstract [en]

    The HCV NS3 protease is essential for replication of the hepatitis C virus (HCV) and therefore constitutes a promising new drug target for anti-HCV therapy. Several potent and promising HCV NS3 protease inhibitors, some of which display low nanomolar activities, were identified from a series of novel inhibitors incorporating a trisubstituted cyclopentane dicarboxylic acid moiety as a surrogate for the widely used N-acyl-(4R)-hydroxyproline in the P2 position.

    Keywords
    HCV, NS3, Protease inhibitor, Cyclopentane-derived P2 scaffold
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-14308 (URN)10.1016/j.bmc.2006.04.008 (DOI)
    Available from: 2007-02-21 Created: 2007-02-21 Last updated: 2017-12-13Bibliographically approved
    2. Potent Macrocyclic Inhibitors of the Hepatitis C Virus NS3 Protease. Use of Cyclopentane and Cyclopentene Derived P2-Scaffolds
    Open this publication in new window or tab >>Potent Macrocyclic Inhibitors of the Hepatitis C Virus NS3 Protease. Use of Cyclopentane and Cyclopentene Derived P2-Scaffolds
    Show others...
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:liu:diva-14309 (URN)
    Available from: 2007-02-21 Created: 2007-02-21 Last updated: 2010-01-13
  • 21.
    Bäck, Marcus
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Design and Synthesis of Inhibitors Targeting the Hepatitis C Virus NS3 Serine Protease and the Aspartic Protease BACE-12009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis describes the synthesis of molecules designed to inhibit the hepatitis C virus (HCV) NS3 serine protease and the human aspartic protease BACE-1, and it also reports the structure-activity relationships between potential inhibitors and the targeted enzymes. In addition, consideration is given to the class of enzymes known as proteases, as well as the question of why such enzymes can be regarded as suitable targets for developing drugs to combat diseases in general. Some strategies used to design protease inhibitors and the desired properties of such potential drug candidates are also briefly examined.

    Infection with HCV gives rise to a predominantly chronic disease that causes severe liver damage and ultimately leads to cirrhosis and liver cancer, and hence it represents the main factor underlying most of the liver transplants in the developed world. The HCV NS3 serine protease is essential for replication of the virus, and it has become one of the most widely exploited targets for developing anti-HCV inhibitors. The results presented here concern the design and synthesis of linear and macrocyclic NS3 protease inhibitors containing a novel trisubstituted cyclopentane moiety as an N-acyl-(4R)-hydroxyproline bioisostere. Several highly potent compounds were evaluated, including inhibitors with Ki and replicon EC50 values in the subnanomolar and the low nanomolar range, respectively.

    Alzheimer’s disease is a fatal neurodegenerative disorder of the brain. It is characterized by loss of memory and cognition, and is associated with accumulation of plaques and tangles that cause serious impairment and functional decline of brain tissues. The plaques consist mainly of amyloid-β fragments that are generated through two cleavages of amyloid precursor protein (APP). The enzyme responsible for the initial cleavage is the aspartic protease BACE-1 (beta-site APP-cleaving enzyme), which was explored in the current studies as a pharmaceutical target. The synthetic work comprised development of two series of BACE-1 inhibitors with different central core isosteres; a statine-based and a hydroxyethylene-based series. Highly potent inhibitors were produced by varying the substituents coupled to the statine-based central core. X-ray crystallography and molecular modeling enabled analysis of the binding properties of these compounds. In the second series a hydroxyethylene central core was decorated with more advanced P1 substituents with the aim of increasing the binding interactions with the S1 site. This resulted in inhibitors with more drug-like properties and activities in the low micromolar range.

    List of papers
    1. Potent inhibitors of the hepatitis C virus NS3 protease: use of a novel P2 cyclopentane-derived template
    Open this publication in new window or tab >>Potent inhibitors of the hepatitis C virus NS3 protease: use of a novel P2 cyclopentane-derived template
    Show others...
    2006 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 14, no 15, p. 5136-5151Article in journal (Refereed) Published
    Abstract [en]

    The HCV NS3 protease is essential for replication of the hepatitis C virus (HCV) and therefore constitutes a promising new drug target for anti-HCV therapy. Several potent and promising HCV NS3 protease inhibitors, some of which display low nanomolar activities, were identified from a series of novel inhibitors incorporating a trisubstituted cyclopentane dicarboxylic acid moiety as a surrogate for the widely used N-acyl-(4R)-hydroxyproline in the P2 position.

    Keywords
    HCV, NS3, Protease inhibitor, Cyclopentane-derived P2 scaffold
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-14308 (URN)10.1016/j.bmc.2006.04.008 (DOI)
    Available from: 2007-02-21 Created: 2007-02-21 Last updated: 2017-12-13Bibliographically approved
    2. Novel potent macrocyclic inhibitors of the hepatitis C virus NS3 protease: use of cyclopentane and cyclopentene P2-motifs.
    Open this publication in new window or tab >>Novel potent macrocyclic inhibitors of the hepatitis C virus NS3 protease: use of cyclopentane and cyclopentene P2-motifs.
    Show others...
    2007 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 15, no 22, p. 7184-7202Article in journal (Refereed) Published
    Abstract [en]

    Several highly potent novel HCV NS3 protease inhibitors have been developed from two inhibitor series containing either a P2 trisubstituted macrocyclic cyclopentane- or a P2 cyclopentene dicarboxylic acid moiety as surrogates for the widely used N-acyl-(4R)-hydroxyproline in the P2 position. These inhibitors were optimized for anti HCV activities through examination of different ring sizes in the macrocyclic systems and further by exploring the effect of P4 substituent removal on potency. The target molecules were synthesized from readily available starting materials, furnishing the inhibitor compounds in good overall yields. It was found that the 14-membered ring system was the most potent in these two series and that the corresponding 13-, 15-, and 16-membered macrocyclic rings delivered less potent inhibitors. Moreover, the corresponding P1 acylsulfonamides had superior potencies over the corresponding P1 carboxylic acids. It is noteworthy that it has been possible to develop highly potent HCV protease inhibitors that altogether lack the P4 substituent. Thus the most potent inhibitor described in this work, inhibitor 20, displays a K(i) value of 0.41 nM and an EC(50) value of 9 nM in the subgenomic HCV replicon cell model on genotype 1b. To the best of our knowledge this is the first example described in the literature of a HCV protease inhibitor displaying high potency in the replicon assay and lacking the P4 substituent, a finding which should facilitate the development of orally active small molecule inhibitors against the HCV protease.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-17846 (URN)10.1016/j.bmc.2007.07.027 (DOI)17845856 (PubMedID)
    Available from: 2009-04-22 Created: 2009-04-22 Last updated: 2017-12-13Bibliographically approved
    3. Design, synthesis and SAR of potent statine-based BACE-1 inhibitors: exploration of P1 phenoxy and benzyloxy residues.
    Open this publication in new window or tab >>Design, synthesis and SAR of potent statine-based BACE-1 inhibitors: exploration of P1 phenoxy and benzyloxy residues.
    Show others...
    2008 (English)In: Bioorganic & medicinal chemistry, ISSN 1464-3391, Vol. 16, no 21, p. 9471-9486Article in journal (Refereed) Published
    Abstract [en]

    Several BACE-1 inhibitors with low nanomolar level activities, encompassing a statine-based core structure with phenyloxymethyl- and benzyloxymethyl residues in the P1 position, are presented. The novel P1 modification introduced to allow the facile exploration of the S1 binding pocket of BACE-1, delivered highly promising inhibitors.

    Keywords
    Alzheimer’s disease, BACE-1 inhibitors, P1 modifications, Peptidomimetics
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-17848 (URN)10.1016/j.bmc.2008.09.041 (DOI)18842420 (PubMedID)
    Available from: 2009-04-22 Created: 2009-04-22 Last updated: 2009-04-22Bibliographically approved
    4. Design and Synthesis of Hydroxyethylene-Based BACE-1 Inhibitors Incorporating Extended P1 Substituents
    Open this publication in new window or tab >>Design and Synthesis of Hydroxyethylene-Based BACE-1 Inhibitors Incorporating Extended P1 Substituents
    (English)Manuscript (Other academic)
    Abstract [en]

    BACE-1 inhibitors with a hydroxyetylene central core, comprising a methoxy residue in the P1´ position, are presented. Extended P1 substituents were introduced with the aim to explore possible interactions with the S1-S3 pocket. Incorporation of the more advanced P1 substituents produced promising inhibitors in the low micromolar range.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-17849 (URN)
    Available from: 2009-04-22 Created: 2009-04-22 Last updated: 2014-01-09Bibliographically approved
  • 22.
    Bäck, Marcus
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Johansson, Per-Ola
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Wångsell, Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Thorstensson, Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Kvarnström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Ayesa, Susana
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Wähling, Horst
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Pelcman, Mikael
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Jansson, Katarina
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Lindström, Stefan
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Wallberg, Hans
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Classon, Björn
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Rydergård, Christina
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Vrang, Lotta
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Hamelink, Elizabeth
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Hallberg, Anders
    Rosenquist, Åsa
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Samuelsson, Bertil
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden/Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden.
    Novel potent macrocyclic inhibitors of the hepatitis C virus NS3 protease: use of cyclopentane and cyclopentene P2-motifs.2007In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 15, no 22, p. 7184-7202Article in journal (Refereed)
    Abstract [en]

    Several highly potent novel HCV NS3 protease inhibitors have been developed from two inhibitor series containing either a P2 trisubstituted macrocyclic cyclopentane- or a P2 cyclopentene dicarboxylic acid moiety as surrogates for the widely used N-acyl-(4R)-hydroxyproline in the P2 position. These inhibitors were optimized for anti HCV activities through examination of different ring sizes in the macrocyclic systems and further by exploring the effect of P4 substituent removal on potency. The target molecules were synthesized from readily available starting materials, furnishing the inhibitor compounds in good overall yields. It was found that the 14-membered ring system was the most potent in these two series and that the corresponding 13-, 15-, and 16-membered macrocyclic rings delivered less potent inhibitors. Moreover, the corresponding P1 acylsulfonamides had superior potencies over the corresponding P1 carboxylic acids. It is noteworthy that it has been possible to develop highly potent HCV protease inhibitors that altogether lack the P4 substituent. Thus the most potent inhibitor described in this work, inhibitor 20, displays a K(i) value of 0.41 nM and an EC(50) value of 9 nM in the subgenomic HCV replicon cell model on genotype 1b. To the best of our knowledge this is the first example described in the literature of a HCV protease inhibitor displaying high potency in the replicon assay and lacking the P4 substituent, a finding which should facilitate the development of orally active small molecule inhibitors against the HCV protease.

  • 23.
    Bäck, Marcus
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Kvarnström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Rosenquist, Åsa
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Samuelsson, Bertil
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden/Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden.
    Design and Synthesis of Hydroxyethylene-Based BACE-1 Inhibitors Incorporating Extended P1 SubstituentsManuscript (Other academic)
    Abstract [en]

    BACE-1 inhibitors with a hydroxyetylene central core, comprising a methoxy residue in the P1´ position, are presented. Extended P1 substituents were introduced with the aim to explore possible interactions with the S1-S3 pocket. Incorporation of the more advanced P1 substituents produced promising inhibitors in the low micromolar range.

  • 24.
    Bäck, Marcus
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Nyhlén, Jonas
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Kvarnström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Appelgren, Sara
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Borkakoti, Neera
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Jansson, Katarina
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Lindberg, Jimmy
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Nyström, Susanne
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Hallberg, Anders
    Department of Organic Pharmaceutical Chemistry, Uppsala University, BMC, Box 574, S-751 23 Uppsala, Sweden.
    Rosenquist, Åsa
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Samuelsson, Bertil
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden/Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-10691 Stockholm, Sweden.
    Design, synthesis and SAR of potent statine-based BACE-1 inhibitors: exploration of P1 phenoxy and benzyloxy residues.2008In: Bioorganic & medicinal chemistry, ISSN 1464-3391, Vol. 16, no 21, p. 9471-9486Article in journal (Refereed)
    Abstract [en]

    Several BACE-1 inhibitors with low nanomolar level activities, encompassing a statine-based core structure with phenyloxymethyl- and benzyloxymethyl residues in the P1 position, are presented. The novel P1 modification introduced to allow the facile exploration of the S1 binding pocket of BACE-1, delivered highly promising inhibitors.

  • 25.
    Ceasar (Berg), Ina
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Protein Science. Linköping University, The Institute of Technology.
    Jonsson, Maria
    Linköping University, Department of Physics, Chemistry and Biology, Protein Science. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Thor, Stefan
    Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Protein Science. Linköping University, The Institute of Technology.
    Curcumin Promotes A-beta Fibrillation and Reduces Neurotoxicity in Transgenic Drosophila2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 2Article in journal (Refereed)
    Abstract [en]

    The pathology of Alzheimers disease (AD) is characterized by the presence of extracellular deposits of misfolded and aggregated amyloid-beta (A beta) peptide and intraneuronal accumulation of tangles comprised of hyperphosphorylated Tau protein. For several years, the natural compound curcumin has been proposed to be a candidate for enhanced clearance of toxic A beta amyloid. In this study we have studied the potency of feeding curcumin as a drug candidate to alleviate A beta toxicity in transgenic Drosophila. The longevity as well as the locomotor activity of five different AD model genotypes, measured relative to a control line, showed up to 75% improved lifespan and activity for curcumin fed flies. In contrast to the majority of studies of curcumin effects on amyloid we did not observe any decrease in the amount of A beta deposition following curcumin treatment. Conformation-dependent spectra from p-FTAA, a luminescent conjugated oligothiophene bound to A beta deposits in different Drosophila genotypes over time, indicated accelerated pre-fibrillar to fibril conversion of A beta(1-42) in curcumin treated flies. This finding was supported by in vitro fibrillation assays of recombinant A beta(1-42). Our study shows that curcumin promotes amyloid fibril conversion by reducing the pre-fibrillar/oligomeric species of A beta, resulting in a reduced neurotoxicity in Drosophila.

  • 26.
    Dahlgren, Anders
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Branalt, J.
    Brånalt, J., AstraZeneca RandD, Medicinal Chemistry, S-431 83 Mölndal, Sweden.
    Kvarnström, Ingemar
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Nilsson, I.
    AstraZeneca RandD, Medicinal Chemistry, S-431 83 Mölndal, Sweden.
    Musil, D.
    AstraZeneca RandD, Structural Chemistry Laboratory, S-481 83 Mölndal, Sweden.
    Samuelsson, B.
    Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden, Tel.: +46-8-608-3104.
    Synthesis of potential thrombin inhibitors. Incorporation of tartaric acid templates as P2 proline mimetics2002In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 10, no 5, p. 1567-1580Article in journal (Refereed)
    Abstract [en]

    With the objective to prepare novel non-peptidic thrombin inhibitors, bioisosteres of the inhibitory tripeptide D-Phe-Pro-Arg chain have been examined. Thus, the P1 Arg was replaced with p-amidinobenzylamine, an elongated homologue of the same and with 2,5-dichloro benzylamine. The P2-P3, D-Phe-Pro, was replaced with a novel tartaric acid template coupled to a series of readily available, mainly lipophilic, amines. Some of these compounds exhibit promising thrombin inhibition activity in vitro, IC50~5.9 µM. © 2002 Elsevier Science Ltd. All rights reserved.

  • 27.
    Dahlgren, Anders
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Kvarnström, Ingemar
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Vrang, L.
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Hamelink, E.
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Hallberg, A.
    Dept. of Organ. Pharmaceutical Chem., BMC, Uppsala University, S-751 24 Uppsala, Sweden.
    Rosenquist, A.
    Samuelsson, B.
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden, Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden.
    New inhibitors of the malaria aspartyl proteases plasmepsin I and II2003In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 11, no 16, p. 3423-3437Article in journal (Refereed)
    Abstract [en]

    New inhibitors of plasmepsin I and II, the aspartic proteases of the malaria parasite Plasmodium falciparum, are described. From paralell solution phase chemistry, several reversed-statine type isostere inhibitors, many of which are aza-peptides, have been prepared. The synthetic strategy delivers the target compounds in good to high overall yields and with excellent stereochemical control throughout the developed route. The final products were tested for their plasmepsin I and II inhibiting properties and were found to exhibit modest but promising activity. The best inhibitor exhibits Ki values of 250 nM and 1.4 µM for Plm I and II, respectively. © 2003 Elsevier Ltd. All rights reserved.

  • 28.
    Dahlgren, Anders
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Kvarnström, Ingemar
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Vrang, L.
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Hamelink, E.
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden.
    Hallberg, A.
    Dept. of Organ. Pharmaceutical Chem., Uppsala University, Box 596, S-751 24 Uppsala, Sweden.
    Rosenquist, A.
    Samuelsson, B.
    Medivir AB, Lunastigen 7, S-141 44 Huddinge, Sweden, Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden.
    Solid-phase library synthesis of reversed-statine type inhibitors of the malarial aspartyl proteases plasmepsin I and II2003In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 11, no 6, p. 827-841Article in journal (Refereed)
    Abstract [en]

    With the aim to develop inhibitors of the plasmepsin I and II aspartic proteases of the malaria parasite Plasmodium falciparum, we have synthesized sets of libraries from novel reversed-statine isosteres, using a combination of solution phase and solid phase chemistry. The synthetic strategy furnishes the library compounds in good to high overall yields and with excellent stereochemical control throughout the developed route. The products were evaluated for their plasmepsin I and II inhibiting properties and were found to exhibit modest but promising activity. The best inhibitor exhibits an in vitro activity of 28% inhibition of plasmepsin II at an inhibitor concentration of 0.5 µM (Ki for Plm II=5.4 µM). © 2003 Elsevier Science Ltd. All rights reserved.

  • 29.
    Ederth, Thomas
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Ekblad, Tobias
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Pettitt, Michala E
    University of Birmingham.
    Conlan, Sheelagh L
    Newcastle University.
    Du, Chun-Xia
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Callow, Maureen E
    University of Birmingham.
    Callow, James A
    University of Birmingham.
    Mutton, Robert
    Newcastle University.
    Clare, Anthony S
    Newcastle University.
    D`Souza, Fraddry
    TNO Science and Industry.
    Donnelly, Glen
    TNO Science and Industry.
    Bruin, Anouk
    TNO Science and Industry.
    Willemsen, Peter R
    TNO Science and Industry.
    Su, Xueju J
    University of Dundee.
    Wang, Su
    University of Dundee.
    Zhao, Qi
    University of Dundee.
    Hederos, Markus
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Liedberg, Bo
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Resistance of Galactoside-Terminated Alkanethiol Self-Assembled Monolayers to Marine Fouling Organisms2011In: ACS Applied Materials and Interfaces, ISSN 1944-8244, E-ISSN 1944-8252, Vol. 3, no 10, p. 3890-3901Article in journal (Refereed)
    Abstract [en]

    Self-assembled monolayers (SAMs) of galactoside-terminated alkanethiols have protein-resistance properties which can be tuned via the degree of methylation [Langmuir 2005, 21, 2971-2980]. Specifically, a partially methylated compound was more resistant to nonspecific protein adsorption than the hydroxylated or fully methylated counterparts. We investigate whether this also holds true for resistance to the attachment and adhesion of a range of marine species, in order to clarify to what extent resistance to protein adsorption correlates with the more complex adhesion of fouling organisms. The partially methylated galactoside-terminated SAM was further compared to a mixed monolayer of omega-substituted methyl- and hydroxyl-terminated alkanethiols with wetting properties and surface ratio of hydroxyl to methyl groups matching that of the galactoside. The settlement (initial attachment) and adhesion strength of four model marine fouling organisms were investigated, representing both micro- and macrofoulers; two bacteria (Cobetia marina and Marinobacter hydrocarbonoclasticus), barnacle cypris larvae (Balanus amphitrite), and algal zoospores (Ulva linza). The minimum in protein adsorption onto the partially methylated galactoside surface was partly reproduced in the marine fouling assays, providing some support for a relationship between protein resistance and adhesion of marine fouling organisms. The mixed alkanethiol SAM, which was matched in wettability to the partially methylated galactoside SAM, consistently showed higher settlement (initial attachment) of test organisms than the galactoside, implying that both wettability and surface chemistry are insufficient to explain differences in fouling resistance. We suggest that differences in the structure of interfacial water may explain the variation in adhesion to these SAMs.

  • 30.
    Ekeroth, Johan
    et al.
    Linköping University, Department of Physics, Chemistry and Biology.
    Björefors, Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics . Linköping University, The Institute of Technology.
    Borgh, Annika
    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.
    Liedberg, Bo
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics . Linköping University, The Institute of Technology.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Electrochemical Evaluation of the Interfacial Capacitance upon Phosphorylation of Amino Acid Analogue Molecular Films2001In: Analytical Chemistry, ISSN 0003-2700, Vol. 73, no 18, p. 4463-4468Article in journal (Refereed)
    Abstract [en]

    An approach based on electrochemistry to differentiate between phosphorylated and nonphosphorylated amino acid analogues adsorbed on gold is presented. Analogues of serine, threonine, and tyrosine, containing thiohexadecyl headgroups, were synthesized and assembled on gold, and the surface capacitance was evaluated using electrochemical impedance spectroscopy. A procedure for deprotection of tert-butyl phosphate protecting groups, on the monolayer, is also described. Characterizations of the assembled analogues by cyclic voltammetry, infrared spectroscopy, and ellipsometry are used to confirm the insulating properties of the monolayers and the outcome of surface modifications. The results from cyclic voltammetry show good insulating properties for the monolayers even after phosphate deprotection. The infrared measurements reveal well-ordered monolayers, and the thickness from ellipsometry is in good agreement with expectations from molecular modeling. The impedance experiments show a capacitance increase up to 0.6 μF/cm2 as phosphate groups are introduced. The results in this study indicate the possibility of using a surface chemical and impedance spectroscopy approach to detect the kinase/phosphatase activity and kinetics involved in phosphorylation reactions.

  • 31.
    Ekeroth, Johan
    et al.
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Borgh, Annika
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics. Linköping University, The Institute of Technology.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic 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.
    Synthesis and Monolayer Characterization of Phosphorylated Amino Acid Analogs2002In: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 254, no 2, p. 322-330Article in journal (Refereed)
    Abstract [en]

    The synthesis of a series of thiols containing phosphorylated and non-phosphorylated serine, threonine, and tyrosine amino acid residues is described. The synthesized molecules, based on 3-mercaptopropionic acid, were assembled onto gold and subsequently characterized using infrared reflection-absorption spectroscopy, ellipsometry, X-ray photoelectron spectroscopy, and contact angle goniometry. The ellipsometric analysis indicates that they form densely packed and well-oriented monolayers on gold, with thicknesses that are in good agreement with estimated values from space-filling models. The bulky and space-demanding phosphorylated threonine analog was, however, found to be an exception. The increase in layer thickness when adding a phosphate group to the threonine is only 35% of that observed for the two other analogs. A detailed infrared examination of the influence of cation coordination to the phosphorylated serine analog using calcium and magnesium reveals structural similarities to those of the inorganic phosphate compound calcium hydroxy apatite. We furthermore discuss the application of these monolayers as soft templates for biomineralization.

  • 32.
    Ekeroth, Johan
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Björefors, Fredrik
    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.
    Liedberg, Bo
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics. Linköping University, The Institute of Technology.
    Monitoring the interfacial capacitance at self-assembled phosphate monolayers on gold electrodes upon interaction with calcium and magnesium2002In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 74, no 9, p. 1979-1985Article in journal (Refereed)
    Abstract [en]

    Electrochemical impedance spectroscopy has been used to evaluate the change in interracial capacitance upon calcium and magnesium coordination to a phosphate-modified electrode. The phosphate electrode was prepared via immobilization of phosphorylated, thiol-containing, serine analogues onto gold. Upon subjection to calcium and magnesium, a substantial drop in capacitance was observed. Magnesium displayed the largest influence on the capacitance: a 27% capacitance drop was observed upon introduction of a 1 mM solution of magnesium ions. The lowered capacitance is a result of a change in the potential and charge distribution at the film/electrolyte interface as the cations coordinate to the phosphate groups. Moreover, the relationship between electrode potential and capacitance has been investigated and reveals a significant difference between monovalent and divalent cations. As complementary information, infrared reflection absorption spectra of the phosphorylated monolayer having different counterions are presented. The results reported in this paper indicate that the phosphorylated amino acid analogue monolayers could be used in investigations of the biochemically important coordination of calcium and magnesium to phosphates and phosphorylated amino acids.

  • 33.
    Ekeroth, Johan
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology.
    Konradsson, Peter
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Hook, F.
    Höök, F., Department of Applied Physics, Chalmers University of Technology, Göteborg University, SE-412 96 Göteborg, Sweden.
    Bivalent-ion-mediated vesicle adsorption and controlled supported phospholipid bilayer formation on molecular phosphate and sulfate layers on gold2002In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 18, no 21, p. 7923-7929Article in journal (Refereed)
    Abstract [en]

    Strategies to form supported lipid assemblies on organophosphate- and organosulfate-monolayer-modified gold surfaces are described. By varying surface treatment and the Mg2+ (Ca2+) content in a solution containing phosphatidylcholine vesicles, we demonstrate (i) efficient formation of supported phosphatidylcholine bilayers (SPBs), (ii) formation of supported nonruptured phosphatidylcholine vesicles, and (iii) reduced phosphatidylcholine vesicle adsorption. Thus, by simply varying the solution conditions, the system can be tuned to controlled formation of either a SPB, supported nonruptured vesicles, or a surface with fairly low coverage of nonruptured vesicles. The profound effects induced on the system by Mg2+ and Ca2+ are assigned to a combination of ion-coordination to the surface, ion-association to the lipid headgroups, and osmotic pressure.

  • 34.
    Ekeroth, Johan
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology.
    Konradsson, Peter
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Svedhem, S
    Linkoping Univ, Dept Chem, SE-58183 Linkoping, Sweden Chalmers Univ Technol, Dept Phys Chem, Gothenburg, Sweden.
    Hook, F
    Linkoping Univ, Dept Chem, SE-58183 Linkoping, Sweden Chalmers Univ Technol, Dept Phys Chem, Gothenburg, Sweden.
    Formation and functionalization of surface-supported lipid structures: Building artificial cell membranes on a gold surface.2002In: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 224, p. 178-COLL-Conference paper (Other academic)
  • 35.
    Ericsson, Emma
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics. Linköping University, The Institute of Technology.
    Bui, Lan
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Enander, Karin
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics. Linköping University, The Institute of Technology.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic 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.
    Oriented Protein Immobilization by Chelate Associated PhotochemistryManuscript (preprint) (Other academic)
    Abstract [en]

    We demonstrate herein the synthesis, characterization and application of a novel chelateassociated photochemistry (CAP) for oriented and robust attachment of biomolecular ligandsto sensing surfaces. The chelation agent is nitrilotriacetic acid (NTA) which is capable ofcoordinating two histidine (His) molecules in the presence of Nickel. Therefore a ligandmodified with a His-sequence can be attached to NTA to form an oriented assembly ofligands on the sensor surface. The ligand is then covalently bound to the surface via a nearbyphotolabile benzophenone (BP) which attacks C-H bonds upon UV light activation. Theligand is then available for analyte interaction. The synthesized compounds used in this studyare based on the well-known organosulphur surface chemistry for proper attachment to goldsurfaces. Besides the two BP and NTA alkane thiols/disulphides we also synthesized a fillermolecule with an oligo (ethylene glycol) (OEG) tail to fine tune the surface composition andto reduce non-specific binding. Results from surface plasmon resonance (SPR) measurementsusing a Biacore 3000 instrument indicate that up to 55% larger analyte response is obtainedwith CAP as compared to the response obtained with the random orientation achieved byphotoimmobilization alone.

  • 36.
    Ericsson, Emma
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics. Linköping University, The Institute of Technology.
    Enander, Karin
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics. Linköping University, The Institute of Technology.
    Bui, Lan
    Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany.
    Lundström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Applied Physics. Linköping University, The Institute of Technology.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic 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.
    Controlled Orientation and Covalent Attachment of Proteins on Biosensor Surfaces by Chelation Assisted Photoimmobilization2013Manuscript (preprint) (Other academic)
    Abstract [en]

    This report presents a novel method for uniform orientation and covalent attachment of proteins to sensing surfaces, termed Chelation Assisted Photoimmobilization (CAP). Alkanethiols terminated with either nitrilotriacetic acid (NTA), benzophenone (BP) or oligo(ethylene glycol) were synthesized and mixed self-assembled monolayers (SAMs) were prepared on gold and thoroughly characterized by infrared reflection absorption spectroscopy (IRAS), ellipsometry and contact angle goniometry. In the process of CAP, NTA chelates Ni2+ and the complex coordinates a His-tagged ligand in an oriented assembly. The ligand is then photoimmobilized via BP, which forms covalent bonds upon UV light activation. The CAP concept was demonstrated using human IgG-Fc modified with C-terminal hexahistidine tags (His-IgGFc) as the ligand and protein A as the analyte.

    In the development of affinity biosensors, uniform orientation of ligand molecules where all analyte binding sites are accessible is often preferred to random orientation. In order to monitor the effect of ligand orientation on analyte response, the ligand-analyte interaction was quantified by surface plasmon resonance analysis, both in the case of CAP and when the ligand was attached by conventional amine coupling on surfaces presenting NTA. Responses were adjusted for differences in ligand immobilization level using IRAS. The normalized analyte response with randomly oriented ligand was 2.5 times higher than that with ligand immobilized by CAP, probably due to molecular crowding effects on the surface and the fact that His-IgGFc is bivalent for protein A. This is a reminder that many other factors than orientation alone may play a decisive role in analyte binding on biosensor surfaces.

  • 37.
    Falsig, Jeppe
    et al.
    Institute of Neuropathology, Zurich.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Knowles, Tuomas P J
    University of Cambridge.
    Aguzzi, Adriano
    Institute of Neuropathology, Zurich.
    Chemical and biophysical insights into the propagation of prion strains2008In: HFSP JOURNAL, ISSN 1955-2068, Vol. 2, no 6, p. 332-341Article in journal (Refereed)
    Abstract [en]

    Transmissible spongiform encephalopathies (TSEs) are lethal infectious neurodegenerative diseases. TSEs are caused by prions, infectious agents lacking informational nucleic acids, and possibly identical with higher-order aggregates of the cellular glycolipoprotein PrPC. Prion strains are derived from TSE isolates that, even after inoculation into genetically identical hosts, cause disease with distinct patterns of protein aggregate deposition, incubation times, morphology of the characteristic brain damage, and cellular tropism. Most of these traits are relatively stable across serial passages. Here we review current techniques for studying prion strain differences in vivo and in cells, and discuss the strain phenomena in the general context of the knowledge gained from modeling prion fibril growth in vitro and in simple organisms.

  • 38. Frantz, S.E.A.
    et al.
    Mikael, L.A.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Inganäs, Olle
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics.
    Hammarström, Per
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Biochemistry.
    Quantum efficiency and two-photon absorption cross-section of conjugated polyelectrolytes used for protein conformation measurements with applications on amyloid structures2007In: Chemical Physics, ISSN 0301-0104, E-ISSN 1873-4421, Vol. 336, no 2-3, p. 121-126Article in journal (Refereed)
    Abstract [en]

    Amyloid diseases such as Alzheimer's and spongiform encephalopathies evolve from aggregation of proteins due to misfolding of the protein structure. Early disease handling require sophisticated but yet simple techniques to follow the complex properties of the aggregation process. Conjugated polyelectrolytes (CPEs) have shown promising capabilities acting as optical biological sensors, since they can specifically bind to polypeptides both in solution and in solid phase. The structural changes in biomolecules can be monitored by changes of the optical spectra of the CPEs, both in absorption and emission modes. Notably, the studied CPEs possess multi-photon excitation capability, making them potential for in vivo imaging using laser scanning microscopy. Aggregation of proteins depends on concentration, temperature and pH. The optical effect on the molecular probe in various environments must also be investigated if applied in these environments. Here we present the results of quantum efficiency and two-photon absorption cross-section of three CPEs: POMT, POWT and PTAA in three different pH buffer systems. The extinction coefficient and quantum efficiency were measured. POMT was found to have the highest quantum efficiency being approximately 0.10 at pH 2.0. The two-photon absorption cross-section was measured for POMT and POWT and was found to be more than 18-25 times and 7-11 times that of Fluorescein, respectively. We also show how POMT fluorescence can be used to distinguish conformational differences between amyloid fibrils formed from reduced and non-reduced insulin in spectrally resolved images recorded with a laser scanning microscope using both one- and two-photon excitation. © 2007 Elsevier B.V. All rights reserved.

  • 39.
    Fyrner, Timmy
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Modified surfaces using tailor-made oligosaccharides having orthogonal attachments2011In: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 241, p. 107-CARB-Article in journal (Other academic)
    Abstract [en]

    The ability of fabricating surfaces with low non-specific protein adhesion is of great interest in material science. Studies have shown that self-assembled monolayers (SAMs) covered with carbohydrates moieties have protein resistant characteristics and even marine anti-fouling properties.[1,2]The presented results describe the synthesis of oligosaccharides originating from lactose and mannose. We have also set out to investigate if these orthogonally protected oligosaccharides can be used as spacer molecules and their performance in protein adsorption studies. Using the selected divergence enables incorporation into various surface systems e.g. gold nanoparticles, vesicles or as a conjugate between different macromolecules.

    [1] Hederos, M.; Konradsson, P.; Liedberg, B.; Langmuir, 2005, 21, 2971-2980.[2] Fyrner, T.; Konradsson, P.; et. al.; Submitted, 2010.

  • 40.
    Fyrner, Timmy
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.
    Lee, Hung-Hsun
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Mangone, Alberto
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Ekblad, Tobias
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Pettitt, Michala E
    University of Birmingham, UK.
    Callow, Maureen E
    University of Birmingham, UK.
    Callow, James A
    University of Birmingham, UK.
    Conlan, Sheelagh L
    Newcastle University, UK.
    Mutton, Robert
    Newcastle University, UK.
    Clare, Anthony S
    Newcastle Universitym, UK.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Liedberg, Bo
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Ederth, Thomas
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Saccharide-Functionalized Alkanethiols for Fouling-Resistant Self-Assembled Monolayers: Synthesis, Monolayer Properties, and Antifouling Behavior2011In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 27, no 24, p. 15034-15047Article in journal (Refereed)
    Abstract [en]

    We describe the synthesis of a series of mono-, di-, and trisaccharide-functionalized alkanethiols as well as the formation of fouling-resistant self-assembled monolayers (SAMs) from these. The SAls,,Is were characterized using ellipsometry, wetting measurements, and infrared reflection absorption spectroscopy (WAS). We show that the structure of the carbohydrate moiety affects the packing density and that this also alters the alkane chain organization. Upon increasing the size of the sugar moieties (from mono- to di- and trisaccharides), the structural qualities of the monolayers deteriorated with increasing disorder, and for the trisaccharide, slow reorganization dynamics in response to changes in the environmental polarity were observed. The antifouling properties of these SAMs were investigated through protein adsorption experiments from buffer solutions as well as settlement (attachment) tests using two common marine fouling species, zoospores of the green macroalga Ulva linza and cypris larvae of the barnacle Balanus amphitrite. The SAMs showed overall good resistance to fouling by both the proteins and the tested marine organisms. To improve the packing density of the SAMs with bulky headgroups, we employed mixed SAMs where the saccharide-thiols are diluted with a filler molecule having a small 2-hydroxyethyl headgroup. This method also provides a means by which the steric availability of sugar moieties can be varied, which is of interest for specific interaction studies with surface-bound sugars. The results of the surface dilution study and the low nonspecific adsorption onto the SAMs both indicate the feasibility of this approach.

  • 41.
    Fyrner, Timmy
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, Faculty of Science & Engineering.
    Magnusson, Karin
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, Faculty of Science & Engineering.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Aili, Daniel
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics. Linköping University, The Institute of Technology.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Derivatization of a bioorthogonal protected trisaccharide linker: towards multimodal tools for chemical biology2012In: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 23, no 6, p. 1333-1340Article in journal (Refereed)
    Abstract [en]

    When cross-linking biomolecules to surfaces or to other biomolecules, the use of appropriate spacer molecules is of great importance. Mimicking the naturally occurring spacer molecules will give further insight into their role and function, possibly unveil important issues regarding the importance of the specificity of carbohydrate-based anchor moieties, in e.g., glycoproteins and glycosylphosphatidylinositols. Herein, we present the synthesis of a lactoside-based trisaccharide, potentially suitable as a heterobifunctional bioorthogonal linker molecule whereon valuable chemical handles have been conjugated. An amino-derivative having thiol functionality shows promise as novel SPR-surfaces. Furthermore, the trisaccharide has been conjugated to a cholesterol moiety in combination with a fluorophore which successfully assemble on the cell surface in lipid microdomains, possibly lipid-rafts. Finally, a CuI-catalyzed azide-alkyne cycloaddition reaction (CuAAC) confirms the potential use of oligosaccharides as bioorthogonal linkers in chemical biology.

  • 42.
    Fyrner, Timmy
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Svensson, Stefan C.T.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Synthesis of tri-, penta-, and hepta-saccharides, functionalized with Orthogonally N-Protected Amino residues at the reducing and non-reducing ends2012In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 68, no 33, p. 6712-6720Article in journal (Refereed)
    Abstract [en]

    The synthesis of four bifunctionalized orthogonally N-protected oligosaccharides derived from lactose and mannose, intended as cross-linking derivatives, is described. The amino sugar at the non-reducing end is derivatized with an N-Boc-protected glycine moiety, and further connected to either a mannose (1→6) disaccharide or (1→3) lactose units (one, two or three) resulting in tri-, penta-, or heptasaccharides. All of the synthesized oligosaccharides have an Nbenzyloxycarbonyl-aminoethyl residue at the reducing end. The fully orthogonal N-Boc/N-Cbz protection group pattern enables further conjugation/derivatization and results in a hydrophilic cross-linking molecule. It was found that the order of the final synthetic steps were crucial to avoid acyl migration. A suitable amide coupling protocol has been applied to introduce the NBoc-protected glycine moiety in alcoholic solvent. The synthesized oligosaccharides will provide a model system to investigate the influence of length, structure and flexibility. The function of the cross-linked substituents thereby provide valuable insights into the role as a spacer molecule.

  • 43.
    Gabrielsson, Erik O
    et al.
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Tybrandt, Klas
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Hammarström, Per
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Berggren, Magnus
    Linköping University, Department of Science and Technology. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Spatially Controlled Amyloid Reactions Using Organic Electronics2010In: SMALL, ISSN 1613-6810, Vol. 6, no 19, p. 2153-2161Article in journal (Refereed)
    Abstract [en]

    Abnormal protein aggregates, so called amyloid fibrils, are mainly known as pathological hallmarks of a wide range of diseases, but in addition these robust well-ordered self-assembled natural nanostructures can also be utilized for creating distinct nanomaterials for bioelectronic devices. However, current methods for producing amyloid fibrils in vitro offer no spatial control. Herein, we demonstrate a new way to produce and spatially control the assembly of amyloid-like structures using an organic electronic ion pump (OEIP) to pump distinct cations to a reservoir containing a negatively charged polypeptide. The morphology and kinetics of the created proteinaceous nanomaterials depends on the ion and current used, which we leveraged to create layers incorporating different conjugated thiophene derivatives, one fluorescent (p-FTAA) and one conducting (PEDOT-S). We anticipate that this new application for the OEIP will be useful for both biological studies of amyloid assembly and fibrillogenesis as well as for creating new bioelectronic nanomaterials and devices.

  • 44.
    Gabrielsson, Roger
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Electroactive Conjugated Polyelectrolytes Based on EDOT From Synthesis to Organic Electronics2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Conjugated polyelectrolytes (CP) show interesting electrical and optical properties for organic electronics as well as for life science applications. Their possibilities of supramolecular assembly with nanowire like misfolded proteins, amyloids, as well as synthetic polypeptides or DNA forming conducting nano composites is highly interesting as being a truly bottom up approach for fabrication of OLEDs, photovoltaic’s as well as logic devices.

    A special class of CPs is that of electroactive cojugated polymers (ECPs), which, due to their structure, will exhibits a unique combination of properties, including the following; electrically conducting, ability to store an electric charge and ability to exchange ions. The positive or negative excess charge can be introduced into the conjugated polymer by means of chemical or electrochemical oxidation/reduction (a process called doping) following the polymerization reaction. In order to preserve overall electroneutrality of the polymer during introduction of excess charge, ionexhange processes occurs between the polymer phase and the surrounding electrolyte solution. This charge/discharge process can be utilized for application such as; pseudo super capacitors (energy storage through oxidation/reduction processes), electro mechanical actuators (convert electrical energy to mechanical energy) and sensors (converts a chemical signal to electrical conductivity).

    In this thesis we describes the synthetic challenges with ECPs for applications vide supra. These mostly relates to solubility, ionic functionalization, conductivity and macromolecular properties such as size and shape of the ECPs. The key requirement in the synthesis of ECPs is that the conjugated nature of the monomer is conserved in the synthesis process and that insertion of excess charge (doping) can be obtained. This limits both the choice of monomer and the choice of polymerization process. Monomers of great complexity have been synthesized with this careful goal in mind. Furthermore, the development of novel monomers must also target the appropriate functionality for polymerization. As such, most ECP monomers are electron-rich molecules with pendant groups containing pyrroles, thiophenes, or 3,4-ethylenedioxythiophenes. These three well known ECP monomers are excellent additions to conjugated systems as they typically enable electrochemical polymerization and direct the polymerizations toward linear polymers with good stability towards doping.

    The first topic of this thesis we demonstrate how we can obtain water soluble ECPs with good electrical conductivity by controlling the polymerization techniques and proper ionic functionalization of the monomer. We also show how these polymers can be incorporated by self-assembly with biomolecular templates, such as, DNA and amyloid fibrils, thus generating novel electrically conductive nanowires.

    The second topics of this thesis demonstrate how hydrogels of ECPs can be used as bioand charge storage materials, were we demonstrate electronically controlled cell release for biology applications. Both applications are based on ECPs ability to ionexhange processes during electrochemical redox reactions. As well as ions, solvent and other neutral molecules may enter the film during charge/discharge processes. This cause a swelling or shrinking of the ECP films and the expansion and contraction of the polymer network in conjugation with the sorption/desorption of solvent molecules and ions can be described in terms of mechanical work.

    In the first case we were able to synthesize a water soluble ECP with high amphiphilic character. The polymer was immobilized onto a flexible electrode, suitable for cell growth and subjected to a cell growth media. When the desired cell layer was formed we applied a potential to the flexible electrode. This resulted in that the mechanical work of the immobilized ECP during the applied potential overcame the week adhesive forces to the flexible electrode, which resulted in super swelling and disintegration of the ICP and the cell layer could be harvested.

    In the second case the possibilities of using synthetically modified ECPs as a dopant during electropolymerization of another ECP monomer to obtain a polymer integrated network with high charge density and good charge transport properties. We demonstrate how this polymer network can be used as porous electrodes suitable for supercapacitors.

    List of papers
    1. Iron-Catalyzed Polymerization of Alkoxysulfonate-Functionalized 3,4-Ethylenedioxythiophene Gives Water-Soluble Poly(3,4-ethylenedioxythiophene) of High Conductivity
    Open this publication in new window or tab >>Iron-Catalyzed Polymerization of Alkoxysulfonate-Functionalized 3,4-Ethylenedioxythiophene Gives Water-Soluble Poly(3,4-ethylenedioxythiophene) of High Conductivity
    Show others...
    2009 (English)In: Chemistry of Materials, ISSN 0897-4756, E-ISSN 1520-5002, Vol. 21, no 9, p. 1815-1821Article in journal (Refereed) Published
    Abstract [en]

    Chemical polymerization of a 3,4-ethylenedioxythiophene derivative bearing a sulfonate group (EDOTS) is reported. The polymer, PEDOT-S, is fully water-soluble and has been produced by polymerizing EDOT-S in water, using Na2S2O8 and a catalytic amount of FeCl3. Elemental analysis and XPS measurements indicate that PEDOT-S is a material with a substantial degree of self-doping, but also contains free sulfate ions as charge-balancing counterions of the oxidized polymer. Apart from self-doping PEDOT-S, the side chains enable full water solubility of the material; DLS studies show an average cluster size of only 2 nm. Importantly, the solvation properties of the PEDOT-S are reflected in spin-coated films, which show a surface roughness of 1.2 nm and good conductivity (12 S/cm) in ambient conditions. The electro-optical properties of this material are shown with cyclic voltammetry and spectroelectrochemical experiment reveals an electrochromic contrast (similar to 48% at lambda(max) = 606 nm).

    Place, publisher, year, edition, pages
    American Chemical Society (ACS), 2009
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-18398 (URN)10.1021/cm801512r (DOI)000265781000012 ()
    Available from: 2009-05-25 Created: 2009-05-25 Last updated: 2017-12-13Bibliographically approved
    2. Electrochemical Devices Made from Conducting Nanowire Networks Self-Assembled from Amyloid Fibrils and Alkoxysulfonate PEDOT
    Open this publication in new window or tab >>Electrochemical Devices Made from Conducting Nanowire Networks Self-Assembled from Amyloid Fibrils and Alkoxysulfonate PEDOT
    2008 (English)In: Nano letters (Print), ISSN 1530-6984, E-ISSN 1530-6992, Vol. 8, no 6, p. 1736-1740Article in journal (Refereed) Published
    Abstract [en]

    Proteins offer an almost infinite number of functions and geometries for building nanostructures. Here we have focused on amyloid fibrillar proteins as a nanowire template and shown that these fibrils can be coated with the highly conducting polymer alkoxysulfonate PEDOT through molecular self-assembly in water. Transmission electron microscopy and atomic force microscopy show that the coated fibers have a diameter around 15 nm and a length/thickness aspect ratio >1:1000 . We have further shown that networks of the conducting nanowires are electrically and electrochemically active by constructing fully functional electrochemical transistors with nanowire networks, operating at low voltages between 0 and 0.5 V.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-17660 (URN)10.1021/nl0808233 (DOI)
    Available from: 2009-04-08 Created: 2009-04-08 Last updated: 2017-12-13
    3. Electronic control of cell detachment using a self-doped conducting polymer
    Open this publication in new window or tab >>Electronic control of cell detachment using a self-doped conducting polymer
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    2011 (English)In: Advanced Materials, ISSN 0935-9648, E-ISSN 1521-4095, Vol. 23, no 38, p. 4403-4408Article in journal (Refereed) Published
    Abstract [en]

    An electronic detachment technology based on thin films of a poly(3,4-ethylene-dioxythiophene) derivative is evaluated for controlled release of human epithelial cells. When applying a potential of 1 V, the redox-responsive polymer films detach and disintegrate and at the same time release cells cultured on top in the absence of any enzymatic treatment with excellent preservation of membrane proteins and cell viability.

    Place, publisher, year, edition, pages
    Wiley-Blackwell, 2011
    Keywords
    bioelectronics;cell detachment;conducting polymers;electrochemistry;polymerization
    National Category
    Polymer Chemistry Cell Biology
    Identifiers
    urn:nbn:se:liu:diva-72170 (URN)10.1002/adma.201101724 (DOI)000297007000009 ()21960476 (PubMedID)
    Available from: 2011-11-21 Created: 2011-11-21 Last updated: 2017-12-08
    4. Electronic Polymers and DNA Self-assembled in Nanowire Transistors
    Open this publication in new window or tab >>Electronic Polymers and DNA Self-assembled in Nanowire Transistors
    2013 (English)In: Small, ISSN 1613-6810, E-ISSN 1613-6829, Vol. 9, no 3, p. 363-368Article in journal (Refereed) Published
    Abstract [en]

    In this study the fully acidic form of PEDOT-S was used for the purpose of self-assembly onto DNA. We have previously shown that PEDOT-S is a short polymer that is self-doped with !1/3 of the sulfonate side groups acting as the self-doping sites (see supporting info.). The remaining sulfonate groups contribute to a net anionic charge, and a water-soluble polymer, with an intrinsic bulk conductivity of around 30 S/cm. It has been shown that PEDOT-S can bind to oppositely charged cationic amyloid protein structures in water and form conducting nano fibrillar networks, and it has also been shown to form hybrid structures with synthetic peptides, and gold nanoparticles.

    Place, publisher, year, edition, pages
    Wiley-VCH Verlag Berlin, 2013
    Keywords
    Organic electronics, conducting polymers, DNA nanotechnology, molecular selfassembly, organic electrochemical transistors
    National Category
    Natural Sciences Engineering and Technology
    Identifiers
    urn:nbn:se:liu:diva-81344 (URN)10.1002/smll.201201771 (DOI)000314547200005 ()
    Note

    Funding Agencies|Strategic Research Foundation SSF through the program OPEN||

    Available from: 2012-09-12 Created: 2012-09-12 Last updated: 2017-12-07Bibliographically approved
    5. Hydrogels of polypyrrole and self doped PEDOT for porous electrodes and supercapacitors
    Open this publication in new window or tab >>Hydrogels of polypyrrole and self doped PEDOT for porous electrodes and supercapacitors
    Show others...
    2012 (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The aim of this work is to extend the knowledge of the mechanism of electropolymerization of pyrrole and PEDOT-S by means of in situ electrochemical quartz microbalance with dissipation studies (EQCM-D), which allow us to evaluate the chemical and physical processes during electrochemical deposition of these conductive polymer composites. Meanwhile, the relationship between the morphology of the films and the mechanism of the electropolymerization of pyrrole in presence of PEDOT-S will be discussed. The resulting material is electroactive, black and conducting. This material is a polymer composite where doped polypyrrole chains are found in an environment of doped PEDOT-S chains. They can be identified through the cyclic voltammetry studies of the composite, through element composition and through their optical signatures in electrochromism. The composite has properties suitable for a supercapacitor electrode, and capacitance of up to 650 F/g has been obtained.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-81346 (URN)
    Available from: 2012-09-12 Created: 2012-09-12 Last updated: 2012-09-12Bibliographically approved
  • 45.
    Gabrielsson, Roger H
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Milczarewic, Grzegorz
    Institute of Chemistry and Technical Electrochemistry, Poznan University of Technology, Poland.
    Nagarajuc, D. H
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Inganäs, Olle
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Hydrogels of polypyrrole and self doped PEDOT for porous electrodes and supercapacitors2012Manuscript (preprint) (Other academic)
    Abstract [en]

    The aim of this work is to extend the knowledge of the mechanism of electropolymerization of pyrrole and PEDOT-S by means of in situ electrochemical quartz microbalance with dissipation studies (EQCM-D), which allow us to evaluate the chemical and physical processes during electrochemical deposition of these conductive polymer composites. Meanwhile, the relationship between the morphology of the films and the mechanism of the electropolymerization of pyrrole in presence of PEDOT-S will be discussed. The resulting material is electroactive, black and conducting. This material is a polymer composite where doped polypyrrole chains are found in an environment of doped PEDOT-S chains. They can be identified through the cyclic voltammetry studies of the composite, through element composition and through their optical signatures in electrochromism. The composite has properties suitable for a supercapacitor electrode, and capacitance of up to 650 F/g has been obtained.

  • 46.
    Garegg, P.J.
    et al.
    Arrhenius Laboratory, Department of Organic Chemistry, Stockholm University, S-106 91 Stockholm, Sweden.
    Johansson, K.-J.
    Arrhenius Laboratory, Department of Organic Chemistry, Stockholm University, S-106 91 Stockholm, Sweden.
    Konradsson, Peter
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Lindberg, B.
    Arrhenius Laboratory, Department of Organic Chemistry, Stockholm University, S-106 91 Stockholm, Sweden.
    Trumpakaj, Z.
    Department of Chemistry, University of Gdansk, PL-80-952 Gdansk, Poland.
    Transglucosidation of methyl and ethyl D-glucopyranosides by alcoholysis2002In: Carbohydrate Research, ISSN 0008-6215, E-ISSN 1873-426X, Vol. 337, no 6, p. 517-521Article in journal (Refereed)
    Abstract [en]

    The transglucosidations of methyl 4-O-methyl-a- and -ß-D-glucopyranoside in ethanolic camphor-10-sulfonic acid, and of ethyl 4-O-methyl-a- and -ß-D-glucopyranoside in methanolic camphor-10-sulfonic acid, have been studied. Samples were removed at intervals and the proportions of the glucosides determined by GC of their acetates. The results show that the anomer with the inverted configuration predominates in the initially formed product (˜59-70%). This indicates that all the studied reactions proceed via the same mechanism, involving exocyclic C-O cleavage and formation of a glucopyranosylium ion, but that the eliminated alcohol exerts some steric hindrance, which favors the approach of the other alcohol from the opposite side. © 2002 Published by Elsevier Science Ltd.

  • 47.
    Göransson, Anna-Lena
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Otieno, Mildred
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Johansson, Leif B. G.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Nilsson, K. Peter R
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Brorsson, Ann-Christin
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology. Linköping University, The Institute of Technology.
    Dissecting the Aggregation Events of Alzheimer’s disease Associated Aβ peptide Variants by the Combined use of Different Fluorescent ProbesManuscript (preprint) (Other academic)
    Abstract [en]

    The formation of soluble prefibrillar oligomeric species of the amyloid β peptide (Aβ) has been implicated as a causative agent in the development of Alzheimer’s disease (AD). It is therefore important to characterize the properties of these aggregates, which precede the formation of amyloid fibrils. We studied the in vitro aggregation process of two Aβ40 peptide variants through the combined use of four different fluorescent probes and transmission electron microscopy. Previous studies have shown that these two studied Aβ40 variants exhibit different levels of neurodegeneration when expressed in the central nervous system of Drosophila melanogaster. In the present study, we demonstrate distinct differences in aggregate morphology and their binding properties to different fluorescent probes during in vitro fibrillation of these Aβ peptides. Our results indicate a potential link between the observed neurodegenerative properties and the biophysical properties of distinct aggregated Aβ species.

  • 48.
    Hamedi, Mahiar
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Elfwing, Anders
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Gabrielsson, Roger H
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Inganäs, Olle
    Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, The Institute of Technology.
    Electronic Polymers and DNA Self-assembled in Nanowire Transistors2013In: Small, ISSN 1613-6810, E-ISSN 1613-6829, Vol. 9, no 3, p. 363-368Article in journal (Refereed)
    Abstract [en]

    In this study the fully acidic form of PEDOT-S was used for the purpose of self-assembly onto DNA. We have previously shown that PEDOT-S is a short polymer that is self-doped with !1/3 of the sulfonate side groups acting as the self-doping sites (see supporting info.). The remaining sulfonate groups contribute to a net anionic charge, and a water-soluble polymer, with an intrinsic bulk conductivity of around 30 S/cm. It has been shown that PEDOT-S can bind to oppositely charged cationic amyloid protein structures in water and form conducting nano fibrillar networks, and it has also been shown to form hybrid structures with synthetic peptides, and gold nanoparticles.

  • 49.
    Hammarström, Per
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Simon, Rozalyn
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, Faculty of Science & Engineering.
    Nyström, Sofie
    Linköping University, Department of Physics, Chemistry and Biology, Biochemistry. Linköping University, The Institute of Technology.
    Konradsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Åslund, Andreas
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Nilsson, Peter
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    A Fluorescent Pentameric Thiophene Derivative Detects in Vitro-Formed Prefibrillar Protein Aggregates2010In: BIOCHEMISTRY, ISSN 0006-2960, Vol. 49, no 32, p. 6838-6845Article in journal (Refereed)
    Abstract [en]

    Protein aggregation is associated with a wide range of diseases, and molecular probes that are able to detect a diversity of misfolded protein assemblies are of great importance. The identification of prefibrillar states preceding the formation of well-defined amyloid fibrils is of particular interest both because of their likely role in the mechanism of fibril formation and because of the growing awareness that these species are likely to play a critical role in the pathogenesis of protein deposition diseases. Herein, we explore the use of an anionic oligothiophene derivative, p-FTAA, for detection of prefibrillar protein aggregates during in vitro fibrillation of three different amyloidogenic proteins (insulin, lysozyme, and prion protein). p-FTAA generally detected prefibrillar protein aggregates that could not be detected by thioflavine T fluorescence and in addition showed high fluorescence when bound to mature fibrils. Second, the kinetics of protein aggregation or the formation of amyloid fibrils of insulin was not extensively influenced by the presence of various concentrations of p-FTAA. These results establish the use of p-FTAA as an additional tool for studying the process of protein aggregation.

  • 50.
    Hederos (Håkansson), Sofia
    et al.