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Kihlberg, Jan
Publications (10 of 45) Show all publications
Snir, O., Bäcklund, J., Boström, J., Andersson, I., Kihlberg, J., Buckner, J. H., . . . Malmström, V. (2012). Multifunctional T cell reactivity with native and glycosylated type II collagen in rheumatoid arthritis. Arthritis and Rheumatism, 64(8), 2482-2488
Open this publication in new window or tab >>Multifunctional T cell reactivity with native and glycosylated type II collagen in rheumatoid arthritis
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2012 (English)In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, no 8, p. 2482-2488Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
John Wiley & Sons, 2012
National Category
Medical and Health Sciences Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-58909 (URN)10.1002/art.34459 (DOI)000306906500008 ()
Available from: 2012-09-07 Created: 2012-09-06 Last updated: 2018-06-08Bibliographically approved
Andersson, I. E., Andersson, C. D., Batsalova, T., Dzhambazov, B., Holmdahl, R., Kihlberg, J. & Linusson, A. (2011). Design of glycopeptides used to investigate class II MHC binding and T-Cell responses associated with autoimmune arthritis. PLoS ONE, 6(3), e17881
Open this publication in new window or tab >>Design of glycopeptides used to investigate class II MHC binding and T-Cell responses associated with autoimmune arthritis
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2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 3, p. e17881-Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Public Library of Science, 2011
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-41050 (URN)10.1371/journal.pone.0017881 (DOI)21423632 (PubMedID)
Note

Vid avhandlingens utgivning manuskript med annan titel: "Design of glycopeptide chemical probes used to investigate multiresponses associated with autoimmune arthritis"

Available from: 2011-03-17 Created: 2011-03-17 Last updated: 2018-06-08Bibliographically approved
Andersson, I. E., Batsalova, T., Haag, S., Dzhambazov, B., Holmdahl, R., Kihlberg, J. & Linusson, A. (2011). (E)-Alkene and Ethylene Isosteres Substantially Alter the Hydrogen-Bonding Network in Class II MHC Aq/Glycopeptide Complexes and Affect T-Cell Recognition. Journal of the American Chemical Society, 133(36), 14368-14378
Open this publication in new window or tab >>(E)-Alkene and Ethylene Isosteres Substantially Alter the Hydrogen-Bonding Network in Class II MHC Aq/Glycopeptide Complexes and Affect T-Cell Recognition
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2011 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 133, no 36, p. 14368-14378Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
American Chemical Society, 2011
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-42072 (URN)10.1021/ja2038722 (DOI)
Available from: 2011-04-05 Created: 2011-04-05 Last updated: 2018-06-08Bibliographically approved
Andersson, I. E., Batsalova, T., Dzhambazov, B., Edvinsson, L., Holmdahl, R., Kihlberg, J. & Linusson, A. (2010). Oxazole-modified glycopeptides that target arthritis-associated class II MHC Aq and DR4 proteins. Organic and biomolecular chemistry, 8(13), 2931-2940
Open this publication in new window or tab >>Oxazole-modified glycopeptides that target arthritis-associated class II MHC Aq and DR4 proteins
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2010 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 8, no 13, p. 2931-2940Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
RSC Publishing, 2010
Identifiers
urn:nbn:se:umu:diva-35270 (URN)10.1039/c003640d (DOI)000278824700008 ()20485848 (PubMedID)
Available from: 2010-08-11 Created: 2010-08-11 Last updated: 2018-06-08Bibliographically approved
Saitton, S., Del Tredici, A. L., Saxin, M., Stenström, T., Kihlberg, J. & Luthman, K. (2008). Synthesis and evaluation of novel pyridine based PLG tripeptidomimetics. Organic and biomolecular chemistry, 6(9), 1647-1654
Open this publication in new window or tab >>Synthesis and evaluation of novel pyridine based PLG tripeptidomimetics
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2008 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 6, no 9, p. 1647-1654Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2008
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-9678 (URN)10.1039/b718058f (DOI)000255062300019 ()18421399 (PubMedID)
Available from: 2008-05-19 Created: 2008-05-19 Last updated: 2019-08-07Bibliographically approved
Pudelko, M., Kihlberg, J. & Elofsson, M. (2007). Application of gel-phase 19F NMR spectroscopy for optimization of solid-phase synthesis of a hydrophobic peptide from the signal sequence of the mucin MUC1. Journal of Peptide Science, 13(5), 354-361
Open this publication in new window or tab >>Application of gel-phase 19F NMR spectroscopy for optimization of solid-phase synthesis of a hydrophobic peptide from the signal sequence of the mucin MUC1
2007 (English)In: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 13, no 5, p. 354-361Article in journal (Refereed) Published
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.

Keywords
solid-phase peptide synthesis, difficult sequence, gel-phase 19F NMR, pseudo proline
Identifiers
urn:nbn:se:umu:diva-12721 (URN)doi:10.1002/psc.850 (DOI)
Available from: 2008-05-19 Created: 2008-05-19 Last updated: 2018-06-09Bibliographically approved
Blomberg, D., Fex, T., Xue, Y., Brickmann, K. & Kihlberg, J. (2007). Design, synthesis and biological evaluation of thrombin inhibitors based on a pyridine scaffold.. Organic and biomolecular chemistry, 5(16), 2599-605
Open this publication in new window or tab >>Design, synthesis and biological evaluation of thrombin inhibitors based on a pyridine scaffold.
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2007 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 5, no 16, p. 2599-605Article in journal (Other academic) Published
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.

Identifiers
urn:nbn:se:umu:diva-5964 (URN)doi:10.1039/b705344d (DOI)18019535 (PubMedID)
Available from: 2007-12-04 Created: 2007-12-04 Last updated: 2018-06-09Bibliographically approved
Johansson, S. M., Nilsson, E. C., Elofsson, M., Ahlskog, N., Kihlberg, J. & Arnberg, N. (2007). Multivalent sialic acid conjugates inhibit adenovirus type 37 from binding to and infecting human corneal epithelial cells. Antiviral Research, 73(2), 92-100
Open this publication in new window or tab >>Multivalent sialic acid conjugates inhibit adenovirus type 37 from binding to and infecting human corneal epithelial cells
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2007 (English)In: Antiviral Research, ISSN 0166-3542, E-ISSN 1872-9096, Vol. 73, no 2, p. 92-100Article in journal (Refereed) Published
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.

Keywords
Adenovirus, EKC, Sialic acid, Multivalent
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-12970 (URN)10.1016/j.antiviral.2006.08.004 (DOI)
Available from: 2007-05-11 Created: 2007-05-11 Last updated: 2018-06-09Bibliographically approved
Andersson, I. E., Dzhambazov, B., Holmdahl, R., Linusson, A. & Kihlberg, J. (2007). Probing molecular interactions within Class II MHC Aq/Glycopeptide/T-Cell Receptor Complexes associated with Collagen-Induced Arthritis. Journal of Medicinal Chemistry, 50(23), 5627-5643
Open this publication in new window or tab >>Probing molecular interactions within Class II MHC Aq/Glycopeptide/T-Cell Receptor Complexes associated with Collagen-Induced Arthritis
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2007 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 50, no 23, p. 5627-5643Article in journal (Refereed) Published
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.

Identifiers
urn:nbn:se:umu:diva-17780 (URN)doi:10.1021/jm0705410 (DOI)
Available from: 2008-05-19 Created: 2008-05-19 Last updated: 2018-06-09Bibliographically approved
Holm, L., Frech, K., Dzhambazov, B., Holmdahl, R., Kihlberg, J. & Linusson, A. (2007). Quantitative Structure-Activity Relationship of Peptides Binding to the Class II Major Histocompatibility Complex Molecule Aq Associated with Autoimmune Arthritis. Journal of Medicinal Chemistry, 50(9), 2049-59
Open this publication in new window or tab >>Quantitative Structure-Activity Relationship of Peptides Binding to the Class II Major Histocompatibility Complex Molecule Aq Associated with Autoimmune Arthritis
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2007 (English)In: Journal of Medicinal Chemistry, Vol. 50, no 9, p. 2049-59Article in journal (Refereed) Published
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.

Identifiers
urn:nbn:se:umu:diva-16104 (URN)doi:10.1021/jm061209b (DOI)
Available from: 2007-08-17 Created: 2007-08-17 Last updated: 2018-06-09Bibliographically approved
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