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  • 1.
    Andersson, Ida E
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Andersson, C David
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Batsalova, Tsvetelina
    Medicinal Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm.
    Dzhambazov, Balik
    Medicinal Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm.
    Holmdahl, Rikard
    Medicinal Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Linusson, Anna
    AstraZeneca R&D Mölndal, Mölndal.
    Design of glycopeptides used to investigate class II MHC binding and T-Cell responses associated with autoimmune arthritis2011Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, nr 3, s. e17881-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The glycopeptide fragment CII259–273 from type II collagen (CII) binds to the murine Aq and human DR4 class II Major Histocompatibility Complex (MHC II) proteins, which are associated with development of murine collagen-induced arthritis (CIA) and rheumatoid arthritis (RA), respectively. It has been shown that CII259–273 can be used in therapeutic vaccination of CIA. This glycopeptide also elicits responses from T-cells obtained from RA patients, which indicates that it has an important role in RA as well. We now present a methodology for studies of (glyco)peptide-receptor interactions based on a combination of structure-based virtual screening, ligand-based statistical molecular design and biological evaluations. This methodology included the design of a CII259–273 glycopeptide library in which two anchor positions crucial for binding in pockets of Aq and DR4 were varied. Synthesis and biological evaluation of the designed glycopeptides provided novel structure-activity relationship (SAR) understanding of binding to Aq and DR4. Glycopeptides that retained high affinities for these MHC II proteins and induced strong responses in panels of T-cell hybridomas were also identified. An analysis of all the responses revealed groups of glycopeptides with different response patterns that are of high interest for vaccination studies in CIA. Moreover, the SAR understanding obtained in this study provides a platform for the design of second-generation glycopeptides with tuned MHC affinities and T-cell responses.

  • 2.
    Andersson, Ida E.
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Batsalova, Tsvetelina
    Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
    Dzhambazov, Balik
    Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
    Edvinsson, Lotta
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Holmdahl, Rikard
    Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Linusson, Anna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Oxazole-modified glycopeptides that target arthritis-associated class II MHC Aq and DR4 proteins2010Ingår i: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 8, nr 13, s. 2931-2940Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The glycopeptide CII259-273, a fragment from type II collagen (CII), can induce tolerance in mice susceptible to collagen-induced arthritis (CIA), which is a validated disease model for rheumatoid arthritis (RA). Here, we describe the design and synthesis of a small series of modified CII259-273 glycopeptides with oxazole heterocycles replacing three potentially labile peptide bonds. These glycopeptidomimetics were evaluated for binding to murine CIA-associated A(q) and human RA-associated DR4 class II major histocompatibility complex (MHC) proteins. The oxazole modifications drastically reduced or completely abolished binding to A(q). Two of the glycopeptidomimetics were, however, well tolerated in binding to DR4 and they also induced strong responses by one or two DR4-restricted T-cell hybridomas. This work contributes to the development of an altered glycopeptide for inducing immunological tolerance in CIA, with the long-term goal of developing a therapeutic vaccine for treatment of RA.

  • 3.
    Andersson, Ida E.
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Batsalova, Tsvetelina
    Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet.
    Haag, Sabrina
    Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet.
    Dzhambazov, Balik
    Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet.
    Holmdahl, Rikard
    Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Linusson, Anna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    (E)-Alkene and Ethylene Isosteres Substantially Alter the Hydrogen-Bonding Network in Class II MHC Aq/Glycopeptide Complexes and Affect T-Cell Recognition2011Ingår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 133, nr 36, s. 14368-14378Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The structural basis for antigen presentation by class II major histocompatibility complex (MHC) proteins to CD4(+) T-cells is important for understanding and possibly treating autoimmune diseases. In the work described in this paper, (E)-alkene and ethylene amide-bond isosteres were used to investigate the effect of removing hydrogen-bonding possibilities from the CII259-270 glycopeptide, which is bound by the arthritis-associated murine A(q) class II MHC protein. The isostere-modified glycopeptides showed varying and unexpectedly large losses of A(q) binding that could be linked to the dynamics of the system. Molecular dynamics (MD) simulations revealed that the backbone of CII259-270 and the A(q) protein are able to form up to 11 hydrogen bonds, but fewer than this number are present at any one time. Most of the strong hydrogen-bond interactions were formed by the N-terminal part of the glycopeptide, i.e., in the region where the isosteric replacements were made. The structural dynamics also revealed that hydrogen bonds were strongly coupled to each other; the loss of one hydrogen-bond interaction had a profound effect on the entire hydrogen-bonding network. The A(q) binding data revealed that an ethylene isostere glycopeptide unexpectedly bound more strongly to A(q) than the corresponding (E)-alkene, which is in contrast to the trend observed for the other isosteres. Analysis of the MD trajectories revealed that the complex conformation of this ethylene isostere was structurally different and had an altered molecular interaction pattern compared to the other A(q)/glycopeptide complexes. The introduced amide-bond isosteres also affected the interactions of the glycopeptide/A(q) complexes with T-cell receptors. The dynamic variation of the patterns and strengths of the hydrogen-bond interactions in the class II MHC system is of critical importance for the class II MHC/peptide/TCR signaling system.

  • 4.
    Andersson, Ida E.
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Dzhambazov, Balik
    Medical Inflammation Research, BMC I11, Lund University, SE-221 84 Lund, Sweden.
    Holmdahl, Rikard
    Medical Inflammation Research, BMC I11, Lund University, SE-221 84 Lund, Sweden.
    Linusson, Anna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Probing molecular interactions within Class II MHC Aq/Glycopeptide/T-Cell Receptor Complexes associated with Collagen-Induced Arthritis2007Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 50, nr 23, s. 5627-5643Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    T cells obtained in a mouse model for rheumatoid arthritis are activated by a glycopeptide fragment from rat type II collagen (CII) bound to the class II major histocompatibility complex Aq molecule. We report a comparative model of Aq in complex with the glycopeptide CII260-267. This model was used in a structure-based design approach where the amide bond between Ala261 and Gly262 in the glycopeptide was selected for replacement with [COCH2], [CH2NH2+], and [(E)-CH=CH] isosteres. Ala-Gly isostere building blocks were then synthesized and introduced in CII260-267 and CII259-273 glycopeptides. The modified glycopeptides were evaluated for binding to the Aq molecule, and the results were interpreted in view of the Aq/glycopeptide model. Moreover, recognition by a panel of T-cell hybridomas revealed high sensitivity for the backbone modifications. These studies contribute to the understanding of the interactions in the ternary Aq/glycopeptide/T-cell receptor complexes that activate T cells in autoimmune arthritis and suggest possibilities for new vaccination approaches.

  • 5.
    Blomberg, David
    et al.
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Brickmann, Kay
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Synthesis of a β-strand mimetic based on a pyridine scaffold2006Ingår i: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 62, nr 47, s. 10937-10944Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A synthetic route to a 2,4-disubstituted pyridine as a potential β-strand mimetic has been developed and applied in the synthesis of a tripeptidomimetic of Leu-Gly-Gly. The pyridine scaffold replaces the central glycine, and is substituted with analogues of leucine and glycine in positions 4 and 2, respectively. 2-Fluoro-4-iodopyridine was chosen as the functionalized scaffold and was substituted with protected leucinal in position 4 via a Grignard exchange reaction using iso-propyl magnesium chloride. The glycine moiety was introduced in position 2 via a nucleophilic aromatic substitution reaction (SNAr) facilitated by microwave irradiation. The synthetic sequence involved 12 steps with an overall yield of 7%.

  • 6.
    Blomberg, David
    et al.
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Fex, Tomas
    Xue, Yafeng
    Brickmann, Kay
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Design, synthesis and biological evaluation of thrombin inhibitors based on a pyridine scaffold.2007Ingår i: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 5, nr 16, s. 2599-605Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    A series of 2,4-disubstituted pyridine derivatives has been designed, synthesised and evaluated as thrombin inhibitors. A Grignard exchange reaction was used to introduce various benzoyl substituents in position 4 of the pyridine ring, where they serve as P3 residues in binding to thrombin. In position 2 of the pyridine ring, a para-amidinobenzylamine moiety was incorporated as P1 residue by an SNAr reaction using ammonia as nucleophile followed by a reductive amination. A crystal structure obtained for one of the compounds in the active site of thrombin revealed that the basic amidine group of the inhibitor was anchored to Asp 189 at the bottom of the S1 pocket. A comparison with melagatran, bound in the active site of thrombin, revealed a good shape match but lack of hydrogen bonding possibilities in the S2–S3 region for the thrombin inhibitors reported in this study.

  • 7.
    Blomberg, David
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Hedenström, Mattias
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Kreye, Paul
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sethson, Ingmar
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Brickmann, Kay
    AstraZeneca R&D Mölndal, Mölndal, Sweden.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Synthesis and conformational studies of a β-turn mimetic incorporated in Leu-enkephalin2004Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 69, nr 10, s. 3500-3508Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A β-turn mimetic in which the four amino acids of a β-turn have been replaced by a 10-membered ring has been designed, synthesized, and subjected to conformational studies. In the mimetic, the intramolecular COi − HNi+3 hydrogen bond that is often found in β-turns has been replaced by an ethylene bridge. In addition, the amide bond between residues i and i + 1 was exchanged for a methylene ether isoster. Such a β-turn mimetic, based on the first four residues of Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu), was prepared in 15 steps. The synthesis relied on a β-azido alcohol prepared in five steps from Cbz-Tyr(tBu)-OH as a key, i-position building block. tert-Butyl bromoacetate, glycine, and a Phe-Leu dipetide were then used as building blocks for positions i + 1, i + 2, and i + 3, respectively. Conformational studies based on 1H NMR data showed that the β-turn mimetic was flexible, but that it resembled a type-II β-turn at low temperature. This low energy conformer closely resembled the structure determined for crystalline Leu-enkephalin.

  • 8.
    Blomberg, David
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Kreye, Paul
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Fowler, Chris
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Brickmann, Kay
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Synthesis and biological evaluation of leucine enkephalin turn mimetics2006Ingår i: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 4, nr 3, s. 416-423Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A cyclic Leu-enkephalin mimetic containing a 7-membered ring, and two linear analogues, has been prepared on solid phase. In the cyclic mimetic the intramolecular (1–4) hydrogen bond found in crystalline Leu-enkephalin has been replaced by an ethylene bridge. In addition, the amide bond between Tyr1 and Gly2 has been replaced by a methylene ether isostere and Gly3 has been deleted. The two linear analogues both contain the methylene ether isostere instead of the Tyr1-Gly2 amide bond and the shorter of the two lacks Gly3. The three compounds, and a β-turn mimetic analogous to the 7-membered turn mimetic but with Gly3 included, were evaluated for specific binding to µ- and δ-opioid receptors in rat brain membranes. With the exception of the β-turn mimetic the three other Leu-enkephalin analogues all bound with varying affinity to the µ- and δ-opioid receptors. From the results it could be concluded that Leu-enkephalin binds in a turn conformation to the opiate receptors, but that this conformation is not a (1–4) β-turn.

  • 9. Dzhambazov, Balik
    et al.
    Holmdahl, Meirav
    Yamada, Hisakata
    Lu, Shemin
    Vestberg, Mikael
    Holm, Björn
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Johnell, Olof
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    The major T cell epitope on type II collagen is glycosylated in normal cartilage but modified by arthritis in both rats and humans2005Ingår i: EUROPEAN JOURNAL OF IMMUNOLOGY, ISSN 0014-2980, Vol. 35, nr 2, s. 357-66Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Type II collagen (CII) is a target for autoreactive T cells in both rheumatoid arthritis and the murine model collagen-induced arthritis. The determinant core of CII has been identified as CII260-270, and the alteration of this T cell epitope by posttranslational modifications is known to be critical for development of arthritis in mice. Using CII-specific T cell hybridomas we have now shown that the immunodominant T cell epitope in the normal (healthy) human and rat joint cartilage is O-glycosylated at the critical T cell receptor recognition position 264 with a mono- or di-saccharide attached to a hydroxylysine. In contrast, in the arthritic human and rat joint cartilage there are both glycosylated and non-glycosylated CII forms. Glycosylated CII from normal cartilage could not be recognized by T cells reactive to peptides having only lysine or hydroxylysine at position 264, showing that antigen-presenting cells could not degrade the O-linked carbohydrate. Thus, the variable forms of the glycosylated epitope are determined by the structures present in cartilage, and these vary during the disease course. We conclude that the chondrocyte determines the structures presented to the immune system and that these structures are different in normal versus arthritic states.

  • 10. Dzhambazov, Balik
    et al.
    Nandakumar, Kutty Selva
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Fugger, Lars
    Holmdahl, Rikard
    Vestberg, Mikael
    Therapeutic Vaccination of Active Arthritis with a Glycosylated Collagen Type II Peptide in Complex with MHC Class II Molecules2006Ingår i: The Journal of Immunology, Vol. 176, s. 1525-33Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In both collagen-induced arthritis (CIA) and rheumatoid arthritis, T cells recognize a galactosylated peptide from type II collagen (CII). In this study, we demonstrate that the CII259–273 peptide, galactosylated at lysine 264, in complex with Aq molecules prevented development of CIA in mice and ameliorated chronic relapsing disease. In contrast, nonglycosylated CII259–273/Aq complexes had no such effect. CIA dependent on other MHC class II molecules (Ar/Er) was also down-regulated, indicating a bystander vaccination effect. T cells could transfer the amelioration of CIA, showing that the protection is an active process. Thus, a complex between MHC class II molecules and a posttranslationally modified peptide offers a new possibility for treatment of chronically active autoimmune inflammation such as rheumatoid arthritis.

  • 11. George, Shaji K
    et al.
    Holm, Björn
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Reis, Celso A
    Schwientek, Tilo
    Clausen, Henrik
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Chemoenzymatic synthesis of derivatives of a T-cell-stimulating peptide which carry tumor-associated carbohydrate antigens2001Ingår i: Journal of the Chemical Society-Perkin Transactions 1, s. 880-5Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Tn (GalNAc-Ser/Thr), T [Gal(13)GalNAc-Ser/Thr], sialyl-Tn [Neu5Ac(26)GalNAc-Ser/Thr] and 2,3-sialyl-T [Neu5Ac(23)Gal(13)GalNAc-Ser/Thr] antigens are examples of tumor-associated carbohydrate antigens expressed by epithelial cancers. We now describe the preparation of 2-bromoethyl glycosides corresponding to the Tn and T antigens in one and five chemical steps (51 and 15% total yield), respectively, starting from N-acetylgalactosamine. The 2-bromoethyl Tn and T glycosides were used to alkylate a homocysteine residue incorporated in a peptide that is able to bind to class I MHC molecules on antigen-presenting cells. The two neoglycopeptides were then converted into glycopeptides which carry the sialyl-Tn and 2,3-sialyl-T antigens by using recombinant sialyltransferases. Interestingly, the sialyltransferases were able to sialylate the Tn and T carbohydrate moieties even though they were linked to the peptide backbone via a spacer instead of being attached to serine or threonine. The four glycopeptides will be used in studies directed towards inducing a carbohydrate-specific T cell response against the Tn, T, sialyl-Tn, and 2,3-sialyl-T antigens.

  • 12.
    Gustafsson, Tomas
    et al.
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Hedenström, Mattias
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Synthesis of a C-Glycoside Analogue of -D-Galactosyl Hydroxylysine and Incorporation in a Glycopeptide from Type II Collagen2006Ingår i: Journal of Organic Chemistry, Vol. 71, nr 5, s. 1911-9Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A stereoselective synthesis of the C-glycoside analogue of -D-galactosyl-(5R,2S)-hydroxylysine (1) has been achieved starting from tetra-O-benzyl-D-galactopyranosyl lactone. The synthesis involved establishment of three stereogenic centers in an unambiguous manner. A facially selective Grignard reaction followed by a silane reduction was used for the anomeric position of the C-galactose residue. An Evans allylation established the configuration of the -aminomethylene group of the hydroxylysine moiety, whereas an asymmetric hydrogenation utilizing Burk's catalyst was used for the -amino acid moiety itself. The synthesis was completed in 17 steps with an overall yield of 18%, resulting in the most complex and functionalized C-glycoside analogue of a naturally occurring glycosylated amino acid prepared to date. In addition, amino acid 1 was incorporated in a glycopeptide from type II collagen known to be crucial for the response of autoimmune T cells obtained in models of rheumatoid arthritis. A preliminary immunological study revealed that four out of five members in a panel of T cell hybridomas were able to recognize this C-linked glycopeptide when presented by Aq class II MHC molecules.

  • 13.
    Gustafsson, Tomas
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Schou, Magnus
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    A total synthesis of hydroxylysine in protected form and investigations of the reductive opening of p-methoxybenzylidene acetals2004Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 69, nr 25, s. 8694-8701Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A synthesis of (2S,5R)-5-hydoxylysine, based on (R)-malic acid and Williams glycine template as chiral precursors, has been developed. This afforded hydroxylysine, suitably protected for direct use in peptide synthesis, in 32% yield over the 13-step sequence. Regioselective reductive opening of a p-methoxybenzylidene acetal and alkylation of the Williams glycine template were key steps in the synthetic sequence. Surprisingly, the regioselectivity in opening of the p-methoxybenzylidene acetal was reversed as compared to what was expected. It was found that this was due to chelation of the trialkylsilyl choride, used as an electrophile in the reductive opening, to an adjacent azide functionality. It was also discovered that an equivalent amount of trialkylsilyl hydride was formed in the reaction, a finding that led to additional mechanistic insight into reductive openings of p-methoxybenzylidene acetals with sodium cyanoborohydride as reducing agent.

  • 14.
    Hedenström, Mattias
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Emtenäs, Hans
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Pemberton, Nils
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Åberg, Veronica
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Hultgren, Scott J.
    Pinkner, Jerome S.
    Tegman, Viola
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sethson, Ingmar
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    NMR studies of interactions between periplasmic chaperones from uropathogenic E-coli and pilicides that interfere with chaperone function and pilus assembly2005Ingår i: ORGANIC & BIOMOLECULAR CHEMISTRY, ISSN 1477-0520, Vol. 3, nr 23, s. 4193-4200Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Adherence of uropathogenic Escherichia coli to host tissue is mediated by pili, which are hair-like protein structures extending from the outer cell membrane of the bacterium. The chaperones FimC and PapD are key components in pilus assembly since they catalyse folding of subunits that are incorporated in type 1 and P pili, respectively, and also transport the subunits across the periplasmic space. Recently, compounds that inhibit pilus biogenesis and interfere with chaperone-subunit interactions have been discovered and termed pilicides. In this paper NMR spectroscopy was used to study the interaction of different pilicides with PapD and FimC in order to gain structural knowledge that would explain the effect that some pilicides have on pilus assembly. First relaxation-edited NMR experiments revealed that the pilicides bound to the PapD chaperone with mM affinity. Then the pilicide-chaperone interaction surface was investigated through chemical shift mapping using N-15-labelled FimC. Principal component analysis performed on the chemical shift perturbation data revealed the presence of three binding sites on the surface of FimC, which interacted with three different classes of pilicides. Analysis of structure-activity relationships suggested that pilicides reduce pilus assembly in E. coli either by binding in the cleft of the chaperone, or by influencing the orientation of the flexible F1-G1 loop, both of which are part of the surface by which the chaperone forms complexes with pilus subunits. It is suggested that binding to either of these sites interferes with folding of the pilus subunits, which occurs during formation of the chaperone-subunit complexes. In addition, pilicides that influence the F1-G1 loop also appear to reduce pilus formation by their ability to dissociate chaperone-subunit complexes.

  • 15.
    Hedenström, Mattias
    et al.
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Holm, Lotta
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Yuan, ZhongQing
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Emtenäs, Hans
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Stereoselective Synthesis of Ψ[CH2O] Pseudodipeptides and Conformational Analysis of a PheΨ[CH2O]Ala Containing Analogue of the Drug Desmopressin2002Ingår i: Bioorganic & Medicinal Chemistry Letters, Vol. 12, nr 6, s. 841-4Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A method for synthesis of XaaΨ[CH2O]Ala/Gly pseudodipeptides in good yields and excellent diastereoselectivity from azido alcohols and (R)-2-chloropropionic acid or tert-butyl bromoacetate has been developed. Insertion of one of the pseudodipeptide building blocks in the peptide drug desmopressin revealed that methylene ether isosteres may have only a minor influence on the secondary structure of peptides.

  • 16.
    Holm, Björn
    et al.
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Baquer, Syed M
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Holm, Lotta
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Holmdahl, Rikard
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Role of the galactosyl moiety of collagen glycopeptides for T-Cell stimulation in a model for rheumatoid arthritis2003Ingår i: Bioorganic & Medicinal Chemistry, Vol. 11, nr 18, s. 3981-7Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Two protected derivatives of β- -galactopyranosyl-5-hydroxy- -lysine, in which HO-4 of galactose has been O-methylated or replaced by fluorine, have been prepared. The building blocks were incorporated at position 264 of the peptide fragment CII259-273 from type II collagen by solid-phase synthesis. The ability of these two glycopeptides, and two CII259-273 glycopeptides in which HO-4 of galactose was either unmodified or deoxygenated, to elicit responses from T-cell hybridomas obtained in a mouse model for rheumatoid arthritis was then determined. The hybridomas were all highly sensitive towards modifications at C-4 of the β- -galactosyl residue of CII259-273, highlighting the role of HO-4 as an important contact point for the T-cell receptor. Most likely, this glycopeptide hydroxyl group is involved in hydrogen bonding with the T-cell receptor.

  • 17.
    Holm, Lotta
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Bockermann, Robert
    Wellner, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Bäcklund, Johan
    Holmdahl, Rikard
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Side-chain and backbone amide bond requirements for glycopeptide stimulation of T-cells obtained in a mouse model for rheumatoid arthritis2006Ingår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 14, nr 17, s. 5921-5932Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Collagen induced arthritis (CIA) is the most studied animal model for rheumatoid arthritis and is associated with the MHC class II molecule Aq. T-cell recognition of a peptide from type II collagen, CII256–270, bound to Aq is a requirement for development of CIA. Lysine 264 is the major T-cell recognition site of CII256–270 and CIA is in particular associated with recognition of lysine 264 after posttranslational hydroxylation and subsequent attachment of a β-d-galactopyranosyl moiety. In this paper we have studied the structural requirements of collagenous glycopeptides required for T-cell stimulation, as an extension of earlier studies of the recognition of the galactose moiety. Synthesis and evaluation of alanine substituted glycopeptides revealed that there are T-cells that only recognise the galactosylated hydroxylysine 264, and no other amino acid side chains in the peptide. Other T-cells also require glutamic acid 266 as a T-cell contact point. Introduction of a methylene ether isostere instead of the amide bond between residues 260 and 261 allowed weaker recognition by some, but not all, of the T-cells. Altogether, these results allowed us to propose a model for glycopeptide recognition by the T-cells, where recognition from one or the other side of the galactose moiety could explain the different binding patterns of the T-cells.

  • 18.
    Holm, Lotta
    et al.
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Frech, Kristina
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Dzhambazov, Balik
    Holmdahl, Rikard
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Linusson, Anna
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Quantitative Structure-Activity Relationship of Peptides Binding to the Class II Major Histocompatibility Complex Molecule Aq Associated with Autoimmune Arthritis2007Ingår i: Journal of Medicinal Chemistry, Vol. 50, nr 9, s. 2049-59Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Presentation of (glyco)peptides by the class II major histocompatibility complex molecule Aq to T cells plays a central role in collagen-induced arthritis, an animal model for the autoimmune disease rheumatoid arthritis. A peptide library was designed using statistical molecular design in amino acid space in which five positions in the minimal mouse collagen type II binding epitope CII260-267 were varied. A substantially reduced peptide library of 24 peptides with diverse and representative molecular characteristics was selected, synthesized, and evaluated for the binding strength to Aq. A multivariate QSAR model was established by correlating calculated descriptors, compressed to its principle properties, with the binding data using partial least-square regression. The model was successfully validated by an external test set. Interpretation of the model provided a molecular property binding motif for peptides interacting with Aq. The information may be useful in future research directed toward new treatments of rheumatoid arthritis.

  • 19.
    Johansson, Susanne M C
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Arnberg, Niklas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Elofsson, Mikael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Wadell, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Multivalent HSA conjugates of 3 '-siallyllactose are potent inhibitors of adenoviral cell attachment and infection2005Ingår i: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 6, nr 2, s. 358-364Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Adenoviruses of serotypes 8, 19 and 37 are the major cause of the severe eye infection EKC (epidemic keratoconjunctivitis). In general, all adenoviruses interact with their cellular receptors through the fibre proteins, which extend from the virus particle. Recently, adenovirus type 37 (Ad37) was found to bind and infect human corneal cells through attachment to carbohydrate structures that carry terminal alpha-(2-3)-linked sialic acids. Herein we present a synthetic route to a 3'-sialyllactose derivative and corresponding multivalent HSA conjugates with varying orders of valency. The potential of these compounds as inhibitors of EKC causing adenovirus of serotype Ad37, was studied with both binding assay and an infectivity assay. The results revealed that these compounds effectively prevent Ad37 from binding to and infecting human corneal epithelial (HCE) cells. Moreover, the inhibition is significantly increased with higher orders of multivalency.

  • 20.
    Johansson, Susanne M C
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Nilsson, Emma C
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Elofsson, Mikael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Ahlskog, Nina
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Arnberg, Niklas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi.
    Multivalent sialic acid conjugates inhibit adenovirus type 37 from binding to and infecting human corneal epithelial cells2007Ingår i: Antiviral Research, ISSN 0166-3542, E-ISSN 1872-9096, Vol. 73, nr 2, s. 92-100Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Adenovirus type 37 is one of the main causative agents of epidemic keratoconjunctivitis. In a series of publications, we have reported that this virus uses sialic acid as a cellular receptor. Here we demonstrate in vitro that on a molar basis, multivalent sialic acid conjugated to human serum albumin prevents adenovirus type 37 from binding to and infecting human corneal epithelial cells 1000-fold more efficiently than monosaccharidic sialic acid. We also demonstrate that the extraordinary inhibitory effect of multivalent sialic acid is due to the ability of this compound to aggregate virions. We conclude that multivalent sialic acid may be a potential new antiviral drug, for use in the treatment of epidemic keratoconjunctivitis caused by the adenoviruses that use sialic acid as cellular receptor.

  • 21.
    Johansson, Susanne
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Nilsson, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Qian, Weixing
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Arnberg, Niklas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Elofsson, Mikael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Design, synthesis and evaluation of N-acyl modified sialic acids as inhibitors of EKC-causing adenovirusesManuskript (preprint) (Övrigt vetenskapligt)
  • 22.
    Kihlberg, Jan
    et al.
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Holmdahl, R.
    Role of glycopeptides from type II collagen in rheumatoid arthritis2005Ingår i: ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, ISSN 0065-7727, Vol. 229Artikel i tidskrift (Övrigt vetenskapligt)
  • 23.
    Larsson, Andreas
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Johansson, Susanne M. C.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Pinkner, Jerome S.
    Hultgren, Scott J.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Linusson, Anna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Multivariate design, synthesis, and biological evaluation of peptide inhibitors of FimC/FimH protein-protein interactions in uropathogenic Escherichia coli2005Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 48, nr 4, s. 935-945Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A peptide library targeting protein-protein interactions crucial for pilus assembly in Gram negative bacteria has been designed using statistical molecular design. A nonamer peptide scaffold was used, with seven positions being varied. The selection was performed in the building block space, and previously known structure-activity data were included in the design procedure. This resulted in a heavily reduced library consisting of 32 peptides which was prepared by solid-phase synthesis. The ability of the peptides to inhibit the protein-protein interaction between the periplasmic chaperone FimC and the pilus adhesin FimH was then determined in an ELISA. Novel peptides with the capability to inhibit the FimC/FimH protein(-)protein interaction to the same extent as the native FimC peptides were discovered. Multivariate QSAR studies of the response in the ELISA gave valuable information on the properties of amino acids which were preferred at the seven positions in the nonamer scaffold. This information can be used in attempts to develop optimized peptides and peptidomimetics that inhibit pilus assembly in pathogenic bacteria.

  • 24.
    Larsson, Andreas
    et al.
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Spjut, Sara
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    An improved procedure for the synthesis of enaminones - Dimer building blocks in beta-strand mimetics2005Ingår i: SYNTHESIS-STUTTGART, ISSN 0039-7881, Vol. 15, s. 2590-6Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    @-Tides have been shown to have the same characteristics as a peptide in the P-strand conformation and to have the ability to self-associate into dimeric beta-sheets. Aza-cyclohexaenaminones, obtained by condensation of a protected azacyclohexa-3,5-dione and amino acid esters, are the key building-blocks in the synthesis of @-tides. An improved three-step synthetic sequence to these enaminones has been developed that takes advantage of microwave-assisted chemistry in two of the steps to enhance the reaction rates. It was also found that the enaminone building blocks can be obtained by direct condensation of the aza-cyclohexa-3,5-dione with amino acid esters, without prior activation of the diketone. Multivariate design was used to optimize this microwave-assisted condensation, resulting in a short reaction time (300 s) and high yields (67-94%).

  • 25. Lindström, Anton
    et al.
    Pettersson, Fredrik
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Berglund, Anders
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Linusson, Anna
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Hierarchical PLS modeling for predicting the binding of a comprehensive set of structurally diverse protein-ligand complexes.2006Ingår i: Journal of Chem Inf Model, ISSN 1549-9596, Vol. 46, nr 3, s. 1154-1167Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A new approach is presented for predicting ligand binding to proteins using hierarchical partial-least-squares regression to latent structures (Hi-PLS). Models were based on information from the 2002 release of the PDBbind database containing (after in-house refinement) high-resolution X-ray crystallography and binding affinity (Kd or Ki) data for 612 protein-ligand complexes. The complexes were characterized by four different descriptor blocks: three-dimensional (3D) structural descriptors of the proteins, protein-ligand interactions according to the Validate scoring function, binding site surface areas, and ligand 2D and 3D descriptors. These descriptor blocks were used in Hi-PLS models, generated using both linear and nonlinear terms, to relate the characterizations to pKd/i. The results show that each of the four descriptor blocks contributed to the model, and the predictions of pKd/i of the internal test set gave a root-mean-square error of prediction (RMSEP) of 1.65. The data were further divided according to the structural classification of the proteins, and Hi-PLS models were constructed for the resulting subclasses. The models for the four subclasses differed considerably in terms of both their ability to predict pKd/i (with RMSEPs ranging from 0.8 to 1.56) and the descriptor block that had the strongest influence. The models were validated with an external test set of 174 complexes from the 2003 release of the PDBbind database. The overall results show that the presented Hi-PLS methodology could facilitate the difficult task of predicting binding affinity.

  • 26. Marcos, Nuno T.
    et al.
    Pinho, Sandra
    Grandela, Catarina
    Cruz, Andrea
    Samyn-Petit, Bénédicte
    Harduin-Lepers, Anne
    Almeida, Raquel
    Silva, Filipe
    Morais, Vanessa
    Costa, Julia
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Clausen, Henrik
    Reis, Celso A.
    Role of the Human ST6GalNAc-I and ST6GalNAc-II in the Synthesis of the Cancer-Associated Sialyl-Tn Antigen2004Ingår i: CANCER RESEARCH, ISSN 0008-5472, Vol. 64, nr 19, s. 7050-7Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Sialyl-Tn antigen (Neu5Acalpha2-6GaINAc-O-Ser/Thr) is highly expressed in several human carcinomas and is associated with carcinoma aggressiveness and poor prognosis. We characterized two human sialyltransferases,(CMP)-C-.-Neu5Ac:GaINAc-R alpha2,6-sialyltransferase (ST6GaINAc)-I and ST6GaINAc-II, that are candidate enzymes for Sialyl-Tn synthases. We expressed soluble recombinant hST6GaINAc-I and hST6GaINAc-II and characterized the substrate specificity of both enzymes toward a panel of glycopeptides, glycoproteins, and other synthetic glycoconjugates. The recombinant ST6GaINAc-I and ST6GaINAc-II showed similar substrate specificity toward glycoproteins and GaINAcalpha-O-Ser/Thr glycopeptides, such as glycopeptides derived from the MUC2 mucin and the HIVgp120. We also observed that the amino acid sequence of the acceptor glycopeptide contributes to the in vitro substrate specificity of both enzymes. We additionally established a gastric cell line, MKN45, stably transfected with the full length of either ST6GaINAc-I or ST6GaINAc-II and evaluated the carbohydrate antigens expression profile induced by each enzyme. MKN45 transfected with ST6GaINAc-I showed high expression of Sialyl-Tn, whereas MKN45 transfected with ST6GaINAc-II showed the biosynthesis of the Sialyl-6T structure [GaIbeta1-3 (Neu5Acalpha2-6)GaINAc-O-Ser/Thr].

    In conclusion, although both enzymes show similar in vitro activities when Tn antigen alone is available, whenever both Tn and T antigens are present, ST6GaINAc-I acts preferentially on Tn antigen, whereas the ST6GaINAc-II acts preferentially on T antigen. Our results show that ST6GaINAc-I is the major Sialyl-Tn synthase and strongly support the hypothesis that the expression of the Sialyl-Tn antigen in cancer cells is due to ST6GaINAc-I activity.

  • 27.
    Mogemark, Mickael
    et al.
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Cirrito, Thomas P
    Sjölin, Petter
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Unanue, Emil R
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Influence of saccharide size on the cellular immune response to glycopeptides2003Ingår i: Organic & Biomolecular Chemistry, Vol. 1, s. 2063-9Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Glycopeptides that bind to MHC molecules on antigen presenting cells may elicit carbohydrate selective T cells. In order to investigate how the cellular immune response depends on the size of the carbohydrate moiety, a trigalactosylated derivative of an immunogenic peptide from hen egg-white lysozyme (HEL52–61) was prepared. Synthesis was accomplished by assembly of an -1,4-linked trigalactose peracetate which was coupled to Fmoc serine. After activation as a pentafluorophenyl ester the resulting building block was used in solid-phase synthesis. In contrast to the corresponding mono- and digalactosylated derivatives of HEL52–61, the trigalactosylated HEL52–61 was not immunogenic. Somewhat surprisingly, this was found to be because the trigalactosyl derivative bound approximately two orders of magnitude weaker to I-Ak MHC molecules than the mono- and digalactosyl peptides. Our observation suggests an explanation for previous findings, which show that glycopeptides isolated from MHC molecules in nature usually carry small saccharides.

  • 28.
    Mogemark, Mickael
    et al.
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Elofsson, Mikael
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Monitoring Solid-Phase Glycoside Synthesis with 19F NMR Spectroscopy2001Ingår i: Organic Letters, Vol. 3, nr 10, s. 1463-6Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A simple and efficient method for monitoring and optimizing carbohydrate synthesis on polymeric support by using 19F NMR spectroscopy is described. The method relies on the use of fluorinated variants of protective groups that are in common use in oligosaccharide synthesis.

  • 29.
    Mogemark, Mickael
    et al.
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Elofsson, Mikael
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Solid-Phase Synthesis of -Gal Epitopes: On-Resin Analysis of Solid-Phase Oligosaccharide Synthesis with 19F NMR Spectroscopy2003Ingår i: Journal of Organic Chemistry, Vol. 68, nr 19, s. 7281-8Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A route for solid-phase synthesis of the -Gal epitopes Gal(1-3)Gal(1-4)Glc and Gal(1-3)Gal(1-4)GlcNAc is described. These trisaccharide antigens are responsible for hyperacute rejection in xenotransplantation of porcine organs. Optimization of the solid-phase synthesis relied on use of fluorinated protective groups for the carbohydrate building blocks and use of a fluorinated linker. This allowed convenient on-resin analysis of the reactions with gel-phase 19F NMR spectroscopy. Conditions were established which allowed reductive ring-opening of 4,6-O-benzylidene acetals to be performed on the solid phase with high regioselectivity to furnish the corresponding 6-O-benzyl ethers. It was found that glycosylations could be conveniently carried out by using thioglycosides as donors with N-iodosuccinimide and trifluoromethanesulfonic acid as the promoter system. With use of these conditions a challenging -glycosidic linkage was successfully installed with complete stereoselectivity in the final glycosylation. It was also established that fluorinated benzoates, benzyl ethers, and benzylidene acetals display almost identical chemical properties as their nonfluorinated counterparts, a finding that is essential for future use of fluorinated protective groups in solid-phase oligosaccharide synthesis.

  • 30.
    Mogemark, Mickael
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Gustafsson, Linda
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Bengtsson, Christoffer
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Elofsson, Mikael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    A fluorinated selenide linker for solid-phase synthesis of n-pentenyl glycosides2004Ingår i: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 6, nr 26, s. 4885-4888Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A fluorine-labeled selenide linker for installing terminal isolated olefins has been synthesized in high overall yield. The resin-bound linker could be glycosylated both with glycosyl trichloroacetimidates and glycosyl fluorides. The linker did not decompose after oxidation with tBuOOH but underwent beta-elimination when it was subjected to heat. This allowed the released n-pentenyl glycoside 15 to be isolated in excellent yield and purity after filtration.

  • 31.
    Mogemark, Mickael
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Gårdmo, Frida
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Tengel, Tobias
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Elofsson, Mikael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Gel-phase F-19 NMR spectral quality for resins commonly used in solid-phase organic synthesis: a study of peptide solid-phase glycosylations2004Ingår i: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 2, s. 1770-1776Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The spectroscopic properties for seven different commercial resins used in solid-phase synthesis were investigated with F-19 NMR spectroscopy. A fluorine-labeled dipeptide was synthesized on each resin, and the resolution of the F-19 resonances in CDCl3, DMSO-d(6), benzene-d(6) and CD3OD were measured with a conventional NMR spectrometer, i.e. without using magic angle spinning. In general, resins containing poly(ethylene glycol) chains (ArgoGel, TentaGel and PEGA) were found to be favorable for the F-19 NMR spectral quality. Three serine containing tri-, penta-, and heptapeptides were then prepared on an ArgoGel resin functionalized with a fluorine-labeled linker. The resin bound peptides were glycosylated utilizing a thiogalactoside glycosyl donor carrying fluorine-labeled protective groups. Monitoring of the glycosylations with gel-phase F-19 NMR spectroscopy allowed each glycopeptide to be formed in similar to80% yield, using a minimal amount of glycosyl donor (3 x 2 equivalents). In addition, it was found that the glycosylation yields were independent of peptide length.

  • 32. Ohlsson, Jörgen
    et al.
    Larsson, Andreas
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Haataja, Sauli
    Alajääski, Jenny
    Stenlund, Peter
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Pinkner, Jerome S,
    Hultgren, Scott J,
    Finne, Jukka
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Nilsson, Ulf J
    Structure activity relationships of galabioside derivatives as inhibitors of E. coli and S. suis adhesins: nanomolar inhibitors of S. suis adhesins2005Ingår i: ORGANIC & BIOMOLECULAR CHEMISTRY, ISSN 1477-0520, Vol. 3, nr 5, s. 886-900Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Four collections of Gal1-4Gal derivatives were synthesised and evaluated as inhibitors of the PapG class II adhesin of uropathogenic Escherichia coli and of the PN and PO adhesins of Streptococcus suis strains. Galabiosides carrying aromatic structures at C1, methoxyphenyl O-galabiosides in particular, were identified as potent inhibitors of the PapG adhesin. Phenylurea derivatisation at C3 and methoxymethylation at O2 of galabiose provided inhibitors of the S. suis strains type PN adhesin with remarkably high affinities (30 and 50 nM, respectively). In addition, quantitative structure–activity relationship models for E. coli PapG adhesin and S. suis adhesin type PO were developed using multivariate data analysis. The inhibitory lead structures constitute an advancement towards high-affinity inhibitors as potential anti-adhesion therapeutic agents targeting bacterial infections.

  • 33.
    Pudelko, Maciej
    et al.
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Elofsson, Mikael
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Application of gel-phase 19F NMR spectroscopy for optimization of solid-phase synthesis of a hydrophobic peptide from the signal sequence of the mucin MUC12007Ingår i: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 13, nr 5, s. 354-361Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This paper describes the manual Fmoc/t-Bu solid-phase synthesis of a difficult nine-residue hydrophobic peptide LLLLTVLTV from one of the signal sequences that flank the tandem repeat of the mucin MUC1. Gel-phase 19F NMR spectroscopy was used as a straightforward method for optimization of the solid-phase synthesis. Different approaches were applied for comparative studies. The strategy based on modified solid-phase conditions using DIC/HOAt for coupling, DBU for Fmoc deprotection, and the incorporation of the pseudo proline dipeptide Fmoc-Leu-Thr(Me, Me pro)-OH as a backbone-protecting group was found to be superior according to gel-phase 19F NMR spectroscopy. Implementation of the optimized Fmoc protocol enabled an effective synthesis of signal peptide LLLLTVLTV.

  • 34.
    Pudelko, Maciej
    et al.
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Lindgren, Anna
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Tengel, Tobias
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Reis, Celso A.
    Elofsson, Mikael
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Formation of lactones from sialylated MUC1 glycopeptides2006Ingår i: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 4, nr 4, s. 713-20Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The tumor-associated carbohydrate antigens TN, T, sialyl TN and sialyl T are expressed on mucins in several epithelial cancers. This has stimulated studies directed towards development of glycopeptide-based anticancer vaccines. Formation of intramolecular lactones involving sialic acid residues and suitably positioned hydroxyl groups in neighboring saccharide moieties is known to occur for glycolipids such as gangliosides. It has been suggested that these lactones are more immunogenic and tumor-specific than their native counterparts and that they might find use as cancer vaccines. We have now investigated if lactonization also occurs for the sialyl TN and T antigens of mucins. It was found that the model compound sialyl T benzyl glycoside , and the glycopeptide Ala-Pro-Asp-Thr-Arg-Pro-Ala from the tandem repeat of the mucin MUC1, in which Thr stands for the 2,3-sialyl-T antigen, lactonized during treatment with glacial acetic acid. Compound gave the 1''--> 2' lactone as the major product and the corresponding 1''--> 4' lactone as the minor product. For glycopeptide the 1''--> 4' lactone constitued the major product, whereas the 1''--> 2' lactone was the minor one. When lactonized was dissolved in water the 1''--> 4' lactone underwent slow hydrolysis, whereas the 1''--> 2' remained stable even after a 30 days incubation. In contrast the corresponding 2,6-sialyl-TN glycopeptide did not lactonize in glacial acetic acid.

  • 35.
    Saitton, Stina
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Del Tredici, Andria L.
    Mohell, Nina
    Vollinga, Roeland C.
    Boström, Dan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Luthman, Kristina
    Design, synthesis and evaluation of a PLG tripeptidomimetic based on a pyridine scaffold2004Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 47, nr 26, s. 6595-6602Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A 2,3,4-substituted pyridine derivative has been identified as a potential tripeptidomimetic scaffold. The design of the scaffold was based on conformational and electrostatic comparisons with a natural tripeptide. The scaffold has been used in the synthesis of a Pro-Leu-Gly-NH2 (PLG) mimetic. The different substituents in the 2-, 3-, and 4-positions of the pyridine ring were introduced via an aromatic nucleophilic substitution reaction, a "halogen-dancing" reaction, and a Grignard coupling of a Boc-protected amino aldehyde, respectively. The synthetic route involves eight steps and provides the mimetic in 20% overall yield. The pyridine based PLG-mimetic was evaluated for its ability to enhance the maximum response of the dopamine agonist N-propylapomorphine (NPA) at human D2 receptors using a cell based assay (the R-SAT assay). The dose-response curve of the mimetic was found to exhibit a down-turn phase, similar to that of PLG. In addition, the mimetic was more potent than PLG to enhance the NPA response; the maximum response was found to be 146% at 10 nM concentration, as compared to 115% for PLG at the same concentration. Interestingly, conformational analysis by molecular modeling showed that the pyridine mimetic cannot adopt a type II -turn conformation that previously has been suggested to be the bioactive conformation of PLG.

  • 36.
    Saitton, Stina
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Göteborg University, Department of Chemistry, Medicinal Chemistry, SE- 412 96, Göteborg, Sweden.
    Del Tredici, Andria L.
    Saxin, Maria
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Göteborg University, Department of Chemistry, Medicinal Chemistry, SE- 412 96, Göteborg, Sweden.
    Stenström, Tobias
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Luthman, Kristina
    Synthesis and evaluation of novel pyridine based PLG tripeptidomimetics2008Ingår i: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 6, nr 9, s. 1647-1654Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Analogues of the pyridine based PLG (Pro-Leu-Gly-NH2) peptidomimetic 1 were synthesized and evaluated as dopamine modulating agents. Modifications in the position corresponding to the leucine side chain in PLG afforded derivatives 2, 3 and 4, substituted with H, Me and Bn instead of the isobutyl group, respectively. Changes in the proline residue produced derivative 5, substituted with a symmetrical piperidine ring instead of the pyrrolidine ring and 6, in which the pyrrolidine ring is connected to the pyridine ring via a hydroxymethyl group instead of a keto function. The peptidomimetics were tested for their ability to enhance the maximal effect of N-propylapomorphine (NPA) at dopamine D2 receptors in the functional cell-based R-SAT assay. Compounds 2, 3, and 4, produced a statistically significant increase in the maximal NPA response at 10 nM (117 ± 6%, 118 ± 6%, and 116 ± 3%, respectively), which is similar to the effect of PLG in this assay, whereas 5 was able to potentiate the response to a similar extent at 1 nM concentration (115 ± 5%). All derivatives produced a bell-shaped dose-response curve and none of the compounds were active at the D2 receptor alone, which indicates that the mechanism behind the activity of both the pyridine based mimetics 1-6 and PLG is the same. Interestingly, L-Pro-D-Leu-Gly-NH2 was found to be more potent than PLG and produced a 119 ± 1% increase in the NPA response at 1 nM.

  • 37.
    Saitton, Stina
    et al.
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Luthman, Kristina
    A synthetic approach to 2,3,4-substituted pyridines useful as scaffolds for tripeptidomimetics2004Ingår i: Tetrahedron, ISSN 0040-4020, Vol. 60, nr 29, s. 6113-20Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The synthesis of 2,3,4-substituted pyridine derivatives useful as scaffolds in the development of peptidomimetics is described. The use of a variety of electrophiles in a halogen-dance reaction to produce 3-alkyl-2-fluoro-4-iodo-pyridine derivatives as ‘functionalized scaffolds’ and the possibility to differentiate between the reactivities of the two halogen handles have been explored. Coupling of amino acid derivatives in the 4-position of the pyridine was found to proceed efficiently by conversion of iodo-pyridine to a Grignard derivative, which was allowed to react with a protected amino aldehyde. Substitution of fluorine in the 2-position of the pyridine was found to be facile with alkoxide nucleophiles, whereas amines were much less reactive.

  • 38.
    Sjölin, Petter
    et al.
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Use of Fluorobenzoyl Protective Groups in Synthesis of Glycopeptides: -Elimination of O-Linked Carbohydrates Is Suppressed2001Ingår i: The Journal of Organic Chemistry, Vol. 66, nr 9, s. 2957-65Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Fluorobenzoyl groups have been investigated as alternatives to acetyl and benzoyl protective groups in carbohydrate and glycopeptide synthesis. D-Glucose and lactose were protected with different fluorobenzoyl groups and then converted into glycosyl bromides in high yields (>80% over two steps). Glycosylation of protected derivatives of serine with these donors gave 1,2-trans glycosides in good yields (~60-70%) and excellent stereoselectivity without formation of ortho esters. The resulting glycosylated amino acid building blocks were then used in solid-phase synthesis of two model O-linked glycopeptides known to be unusually sensitive to -elimination on base-catalyzed deacylation. When either a 3-fluoro- or a 2,5-difluorobenzoyl group was used for protection of each of the two model glycopeptides the extent of -elimination decreased from 80% to 10% and from 50% to 0%, respectively, as compared to when using the ordinary benzoyl group. Fluorobenzoyl groups thus combine the advantages of the benzoyl group in formation of glycosidic bonds (i.e., high stereoselectivity and low levels of ortho ester formation) with the ease of removal characteristic of the acetyl group.

  • 39.
    Snir, Omri
    et al.
    Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden.
    Bäcklund, Johan
    Karolinska Institute, Stockholm, Sweden.
    Boström, Julia
    Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden.
    Andersson, Ida
    Umeå universitet.
    Kihlberg, Jan
    Umeå universitet.
    Buckner, Jane H.
    Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.
    Klareskog, Lars
    Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden.
    Holmdahl, Rikard
    Karolinska Institute, Stockholm, Sweden.
    Malmström, Vivianne
    Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden.
    Multifunctional T cell reactivity with native and glycosylated type II collagen in rheumatoid arthritis2012Ingår i: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, nr 8, s. 2482-2488Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective Type II collagen (CII) is a cartilage-specific protein to which a loss of immune tolerance may trigger autoimmune reactions and cause arthritis. The major T cell epitope on CII, amino acids 259273, can be presented by several HLADRB1*04 alleles in its native or posttranslational glycosylated form. The present study was undertaken to functionally explore and compare CII-autoreactive T cells from blood and synovial fluid of patients with rheumatoid arthritis (RA).

    Methods Peripheral blood was obtained from HLADRB1*04positive RA patients (n = 10) and control subjects (n = 10) and stimulated in vitro with several variants of the CII259273 epitope, i.e., unmodified, glycosylated on Lys-264, glycosylated on Lys-270, or glycosylated on both Lys-264 and Lys-270. Up-regulation of CD154 was used to identify responding T cells. These cells were further characterized by intracellular staining for interleukin-17 (IL-17), interferon-? (IFN?), and IL-2 by flow cytometry. Synovial T cells from RA patients were investigated in parallel.

    Results Multifunctional T cell responses toward all examined variants of the CII259273 peptide could be detected in RA patients and, to a lesser extent, also in healthy HLA-matched controls (P < 0.001). In RA patients, a comparison between blood- and joint-derived T cell function revealed a significant increase in levels of the proinflammatory cytokine IFN? in synovial T cells (P = 0.027). Studies of longitudinally obtained samples showed that T cell responses were sustained over the course of disease, and even included epitope spreading.

    Conclusion The identification of inflammatory T cell responses to both glycosylated and nonglycosylated variants of the major CII epitope in RA patients suggests that CII autoreactivity in RA may be more common than previously recognized.

  • 40. Svensson, Anette
    et al.
    Fex, Tomas
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Preparation of fluorinated linkers: Use of F-19 NMR spectroscopy to establish conditions for solid-phase synthesis of pilicide libraries2000Ingår i: Journal of Combinatorial Chemistry, Vol. 2, nr 736-48Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Three fluorinated linkers which are analogues of linkers commonly used in solid-phase peptide synthesis have been prepared. One of the linkers was used in combination with gel-phase F-19 NMR spectroscopy to develop conditions for solid-phase synthesis of two libraries of pilicides, i.e. compounds designed to inhibit assembly of adhesive pill in uropathogenic Escherichia coli. Attachment to and cleavage from the linker could be monitored based on the chemical shift of the fluorine atom of the linker. In addition, use of the linker as internal standard allowed quantification and optimization of reactions occurring further away from the linker when fluorinated building blocks were employed. Importantly, high-quality F-19 NMR spectra were obtained for compounds linked to a TentaGel resin in a standard NMR tube using an ordinary NMR instrument.

  • 41.
    Svensson, Anette
    et al.
    Organic Chemistry 2 Center for Chemistry and Chemical Engineering Lund Institute of Technology, Lund University P.O. Box 124, SE-221 00 Lund, Sweden.
    Larsson, Andreas
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Emtenäs, Hans
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Hedenström, Mattias
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Fex, Tomas
    3Active Biotech, Lund Research Center P.O. Box 724, SE-220 07 Lund, Sweden.
    Hultgren, Scott J.
    Department of Molecular Microbiology Washington University School of Medicine 660 South Euclid Avenue, St. Louis, MO 63110, USA.
    Pinker, Jerome S.
    Department of Molecular Microbiology Washington University School of Medicine 660 South Euclid Avenue, St. Louis, MO 63110, USA.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Design and evaluation of Pilicides: Potential novel antibacterial agents directed against Uropathogenic Escherichia coli2001Ingår i: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, ChemBioChem (Online), ISSN '1439-7633', Vol. 2, nr 12, s. 915-918Artikel i tidskrift (Refereegranskat)
  • 42.
    Syeda, Baquer M.
    et al.
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Gustafsson, Tomas
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    9-BBN as a convenient protecting group in functionalisation of hydroxylysine2004Ingår i: Tetrahedron, ISSN 0040-4020, Vol. 60, nr 26, s. 5571-5Artikel i tidskrift (Refereegranskat)
    Abstract [sv]

    9-BBN was used for regioselective protection of the α-amino and α-carboxyl groups of (5R)-5-hydroxy--lysine. The resulting 9-BBN complex was then employed in transformations such as N-Cbz protection, azido transfer, O-glycosylation, and O-silylation. Further manipulations led to improved methods for preparation of hydroxylysine and galactosylated hydroxylysine building blocks, suitable for direct use in peptide synthesis under standard Fmoc conditions.

  • 43.
    Tengel, Tobias
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Fex, Tomas
    Emtenäs, Hans
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Almqvist, Fredrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sethson, Ingmar
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Use of 19F NMR spectroscopy to screen chemical libraries for ligands that bind to proteins2004Ingår i: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 2, nr 5, s. 725-731Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Identification of compounds from chemical libraries that bind to macromolecules by use of NMR spectroscopy has gained increasing importance during recent years. A simple methodology based on F-19 NMR spectroscopy for the screening of ligands that bind to proteins, which also provides qualitative information about relative binding strengths and the presence of multiple binding sites, is presented here. A library of fluorinated compounds was assembled and investigated for binding to the two bacterial chaperones PapD and FimC, and also to human serum albumin (HSA). It was found that library members which are bound to a target protein could be identified directly from line broadening and/or induced chemical shifts in a single, one-dimensional F-19 NMR spectrum. The results obtained for binding to PapD using F-19 NMR spectroscopy agreed well with independent studies based on surface plasmon resonance, providing support for the versatility and accuracy of the technique. When the library was titrated to a solution of PapD chemical shift and linewidth changes were observed with increasing ligand concentration, which indicated the presence of several binding sites on PapD and enabled the assessment of relative binding strengths for the different ligands. Screening by F-19 NMR spectroscopy should thus be a valuable addition to existing NMR techniques for evaluation of chemical libraries in bioorganic and medicinal chemistry.

  • 44. Vijayalekshmi, Sarojini
    et al.
    George, Shaji K
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Andersson, Linda K
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Baltzer, Lars
    A surface exposed O-linked galactose residue destabilises the structure of a folded helix–loop–helix dimer2003Ingår i: Organic & Biomolecular Chemistry, Vol. 1, s. 2455-60Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A 42-residue glycopeptide Tn-15 and the corresponding reference polypeptide Thr-15 were designed and synthesized to provide a model system for the study of how glycosylation affects the stability of a molten globule-like protein. Tn-15 and Thr-15 fold into hairpin helix–loop–helix motifs that dimerise to form four-helix bundles and the only difference between the sequences is that Tn-15 carries an O-linked N-acetylgalactosamine residue at the side chain of threonine-15 whereas the sequence Thr-15 is unglycosylated. An analysis of the mean residue ellipticities at 222 nm of the two polypeptides and of the -H chemical shift deviations from random coil values showed that glycosylation reduced the helical content of the polypeptides and increased the dissociation constant of the helix–loop–helix dimer to form monomers. The pH dependencies of the helical content of Tn-15 and Thr-15 differed as that of Thr-15 was largely unaffected by pH in the range from pH 4 to pH 10, whereas Tn-15 lost almost half of the helical content at pH 4 upon raising the pH to 10. No single amino acid residue was found to ionize in a way that could explain the observed pH dependence of Tn-15. The temperature dependence of the mean residue ellipticity of Tn-15 revealed a surprising decrease in helicity at 278 K in comparison with that at 293 K, reminiscent of cold denaturation, that was not observed for the reference four-helix bundle Thr-15.

  • 45.
    Yuan, ZhongQing
    et al.
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Kihlberg, Jan
    Umeå universitet, Teknisk-naturvetenskaplig fakultet, Kemi.
    Synthesis of a beta-turn mimetic suitable for incorporation in the peptide hormone LHRH2005Ingår i: TETRAHEDRON, ISSN 0040-4020, Vol. 61, nr 21, s. 4901-9Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    LHRH is a decapeptide hormone which plays a central role in neuroendocrinology. Conformational studies have suggested that LHRH may adopt a beta-turn involving residues 5-8 when bound to its receptor. A beta-turn mimetic with side chains corresponding to those of a Tyr-Gly-Leu-Orn tetrapeptide has therefore been synthesized for incorporation at positions 5-8 in LHRH. In the turn mimetic, residues i and i + 1 are connected by a psi [CH2O] isostere instead of an amide bond, while a covalent ethylene bridge replaces the hydrogen bond which is often found between residues i and i+3 in beta-turns. The turn mimetic was assembled from three types of building blocks: an azido aldehyde, an Fmoc protected amino acid and a protected dipeptide amine.

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