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  • 1.
    Andersson, Theresa
    et al.
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Lundqvist, Martin
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology . Linköping University, The Institute of Technology.
    Dolphin, Gunnar T.
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    Enander, Karin
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics . Linköping University, The Institute of Technology.
    Jonsson, Bengt-Harald
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Biotechnology . Linköping University, The Institute of Technology.
    Nilsson, Jonas W.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Baltzer, Lars
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
    The binding of human Carbonic Anhydrase II by functionalized folded polypeptide receptors2005In: Chemistry and Biology, ISSN 1074-5521, E-ISSN 1879-1301, Vol. 12, no 11, p. 1245-1252Article in journal (Refereed)
    Abstract [en]

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

  • 2.
    Baltzer, Lars
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology.
    Nilsson, Helena
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Nilsson, Jonas
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    De novo design of proteins - What are the rules?2001In: Chemical Reviews, ISSN 0009-2665, E-ISSN 1520-6890, Vol. 101, no 10, p. 3153-3163Article, review/survey (Refereed)
    Abstract [en]

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

  • 3.
    Baltzer, Lars
    et al.
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology.
    Nilsson, Jonas
    Linköping University, The Institute of Technology. Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry .
    Emerging principles of de novo catalyst design2001In: Current Opinion in Biotechnology, ISSN 0958-1669, E-ISSN 1879-0429, Vol. 12, no 4, p. 355-360Article, review/survey (Refereed)
    Abstract [en]

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

  • 4.
    Nilsson, Jonas
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Design, Synthesis and Characterization of Small Molecule Inhibitors and Small Molecule: Peptide Conjugates as Protein Actors2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis describes different aspects of protein interactions. Initially the function of peptides and their conjugates with small molecule inhibitors on the surface of Human Carbonic Anhydrase isoenzyme II (HCAII) is evaluated.

    The affinities for HCAII of the flexible, synthetic helix-loop-helix motif conjugated with a series of spacered inhibitors were measured by fluorescence spectroscopy and found in the best cases to be in the low nM range. Dissociation constants show considerable dependence on linker length and vary from 3000 nM for the shortest spacer to 40 nM for the longest with a minimum of 5 nM for a spacer with an intermediate length. A rationale for binding differences based on cooperativity is presented and supported by affinities as determined by fluorescence spectroscopy. Heteronuclear Single Quantum Correlation Nuclear Magnetic Resonance (HSQC) spectroscopic experiments with 15N-labeled HCAII were used for the determination of the site of interaction.

    The influence of peptide charge and hydrophobicity was evaluated by surface plasmon resonance experiments. Hydrophobic sidechain branching and, more pronounced, peptide charge was demonstrated to modulate peptide – HCAII binding interactions in a cooperative manner, with affinities spanning almost two orders of magnitude.

    Detailed synthesis of small molecule inhibitors in a general lead discovery library as well as a targeted library for inhibition of α-thrombin is described. For the lead discovery library 160 members emanate from two N4-aryl-piperazine-2-carboxylic acid scaffolds derivatized in two dimensions employing a combinatorial approach on solid support.

    The targeted library was based on peptidomimetics of the D-Phe-Pro-Arg showing the scaffolds cyclopropane-1R,2R-dicarboxylic acid and (4-amino-3-oxo-morpholin-2-yl)- acetic acid as proline isosters. Employing 4-aminomethyl-benzamidine as arginine mimic and different hydrophobic amines and electrophiles as D-phenylalanine mimics resulted in 34 compounds showing IC50 values for α-thrombin ranging more than three orders of magnitude with the best inhibitor showing an IC50 of 130 nM. Interestingly, the best inhibitors showed reversed stereochemistry in comparison with a previously reported series employing a 3-oxo-morpholin-2-yl-acetic acid scaffold.

    List of papers
    1. The binding of human Carbonic Anhydrase II by functionalized folded polypeptide receptors
    Open this publication in new window or tab >>The binding of human Carbonic Anhydrase II by functionalized folded polypeptide receptors
    Show others...
    2005 (English)In: Chemistry and Biology, ISSN 1074-5521, E-ISSN 1879-1301, Vol. 12, no 11, p. 1245-1252Article in journal (Refereed) Published
    Abstract [en]

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

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-13359 (URN)10.1016/j.chembiol.2005.08.018 (DOI)
    Available from: 2005-09-21 Created: 2005-09-21 Last updated: 2017-12-13
    2. Electrostatic and hydrophobic contributions to protein: peptide surface interactions
    Open this publication in new window or tab >>Electrostatic and hydrophobic contributions to protein: peptide surface interactions
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:liu:diva-13360 (URN)
    Available from: 2005-09-21 Created: 2005-09-21 Last updated: 2010-01-13
    3. Solid-phase synthesis of libraries generated from a 4-phenyl-2-carboxy-piperazine Scaffold
    Open this publication in new window or tab >>Solid-phase synthesis of libraries generated from a 4-phenyl-2-carboxy-piperazine Scaffold
    Show others...
    2001 (English)In: Journal of Combinatorial Chemistry, ISSN 2156-8952, Vol. 3, no 6, p. 546-553Article in journal (Refereed) Published
    Abstract [en]

    Strategies for finding novel structures of therapeutical interest are discussed. The rationale for the selection of the two scaffolds N4-(m-aminophenyl)-piperazine-2-carboxylic acid E and N4-(o-aminophenyl)-piperazine-2-carboxylic F is described. The synthesis of the appropriate precursors to scaffold E and F and their use in solid-phase chemistry are described. A 160-member library was produced combining these novel piperazine scaffolds with eight sulfonyl chlorides/acid chlorides and 10 amines. The compound library prepared was analyzed using LC-MS, showing the expected base peak in all wells at an average purity of 82%.

    Place, publisher, year, edition, pages
    American Chemical Society (ACS), 2001
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-13467 (URN)10.1021/cc010013o (DOI)
    Available from: 2005-11-24 Created: 2005-11-24 Last updated: 2018-05-21
    4. Synthesis and SAR of Thrombin Inhibitors Incorporating a Novel 4-Amino-Morpholinone Scaffold: Analysis of X-ray Crystal Structure of Enzyme Inhibitor Complex
    Open this publication in new window or tab >>Synthesis and SAR of Thrombin Inhibitors Incorporating a Novel 4-Amino-Morpholinone Scaffold: Analysis of X-ray Crystal Structure of Enzyme Inhibitor Complex
    Show others...
    2001 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. 46, no 19, p. 3985-4001Article in journal (Refereed) Published
    Abstract [en]

    A 4-amino-2-carboxymethyl-3-morpholinone structural motif derived from malic acid has been used to mimic d-Phe-Pro in the thrombin inhibiting tripeptide d-Phe-Pro-Arg. The arginine in d-Phe-Pro-Arg was replaced by the more rigid P1 truncated p-amidinobenzylamine (Pab). These new thrombin inhibitors were used to probe the inhibitor binding site of α-thrombin. The best candidate in this series of thrombin inhibitors exhibits an in vitro IC50 of 0.130 μM. Interestingly, the stereochemistry of the 4-amino-2-carboxymethyl-3-morpholinone motif is reversed for the most active compounds compared to that of a previously reported 2-carboxymethyl-3-morpholinone series. The X-ray crystal structure of the lead inhibitor cocrystallized with α-thrombin is discussed.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-13362 (URN)10.1021/jm0307990 (DOI)
    Available from: 2005-09-21 Created: 2005-09-21 Last updated: 2009-05-28
  • 5.
    Nilsson, Jonas W.
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Kvarnström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
    Musil, Djordje
    AstraZeneca R&D, Structural Chemistry Laboratory, Mölndal, Sweden.
    Nilsson, Ingemar
    AstraZeneca R&D, Structural Chemistry Laboratory, Mölndal, Sweden.
    Samuelsson, Bertil
    Department of Organic Chemistry, Stockholm University, Stockholm, Sweden and Medivir AB, Huddinge, Sweden.
    Synthesis and SAR of Thrombin Inhibitors Incorporating a Novel 4-Amino-Morpholinone Scaffold: Analysis of X-ray Crystal Structure of Enzyme Inhibitor Complex2001In: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. 46, no 19, p. 3985-4001Article in journal (Refereed)
    Abstract [en]

    A 4-amino-2-carboxymethyl-3-morpholinone structural motif derived from malic acid has been used to mimic d-Phe-Pro in the thrombin inhibiting tripeptide d-Phe-Pro-Arg. The arginine in d-Phe-Pro-Arg was replaced by the more rigid P1 truncated p-amidinobenzylamine (Pab). These new thrombin inhibitors were used to probe the inhibitor binding site of α-thrombin. The best candidate in this series of thrombin inhibitors exhibits an in vitro IC50 of 0.130 μM. Interestingly, the stereochemistry of the 4-amino-2-carboxymethyl-3-morpholinone motif is reversed for the most active compounds compared to that of a previously reported 2-carboxymethyl-3-morpholinone series. The X-ray crystal structure of the lead inhibitor cocrystallized with α-thrombin is discussed.

  • 6.
    Nilsson, Jonas W.
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Thorstensson, Fredrik
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Kvarnström, Ingemar
    Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
    Oprea, Tudor
    Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, Stockholm, Sweden.
    Samuelsson, Bertil
    Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, Stockholm, Sweden.
    Nilsson, Ingemar
    Solid-phase synthesis of libraries generated from a 4-phenyl-2-carboxy-piperazine Scaffold2001In: Journal of Combinatorial Chemistry, ISSN 2156-8952, Vol. 3, no 6, p. 546-553Article in journal (Refereed)
    Abstract [en]

    Strategies for finding novel structures of therapeutical interest are discussed. The rationale for the selection of the two scaffolds N4-(m-aminophenyl)-piperazine-2-carboxylic acid E and N4-(o-aminophenyl)-piperazine-2-carboxylic F is described. The synthesis of the appropriate precursors to scaffold E and F and their use in solid-phase chemistry are described. A 160-member library was produced combining these novel piperazine scaffolds with eight sulfonyl chlorides/acid chlorides and 10 amines. The compound library prepared was analyzed using LC-MS, showing the expected base peak in all wells at an average purity of 82%.

1 - 6 of 6
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