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NMR as a tool in drug research: Structure elucidation of peptidomimetics and pilicide-chaperone complexes
Umeå University, Faculty of Science and Technology, Chemistry.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In the last decades NMR spectroscopy has become an invaluable tool both in academic research and in the pharmaceutical industry. This thesis describes applications of NMR spectroscopy in biomedicinal research for structure elucidation of biologically active peptides and peptidomimetics as well as in studies of ligand-protein interactions.

The first part of this thesis describes the theory and methodology of structure calculations of peptides using experimental restraints derived from NMR spectroscopy. This methodology has been applied to novel mimetics of the peptide hormones desmopressin and Leu-enkephalin. The results of these studies highlight the complicating issue of conformational exchange often encountered in structural determination of peptides and how careful analysis of experimental data as well as optimization of experimental conditions can enable structure determinations in such instances. Although the mimetics of both desmopressin and Leu-enkephalin were found to adopt the wanted conformations, they exhibited no or very poor biological activity. These results demonstrate the difficulties in designing peptidomimetics without detailed structural information of the receptors. A stereoselective synthetic route towards XxxΨ[CH2O]Ala pseudodipeptides is also presented. Such pseudodipeptides can be used as isosteric amide bond replacements in peptides in order to increase their resistance towards proteolytic degradation.

The second part of this thesis describes the study of the interaction between compounds that inhibit pilius assembly, pilicides, and periplasmic chaperones from uropathogenic Escherichia coli. Periplasmic chaperones are key components in assembly of pili, i.e. hair-like protein complexes located on the surface of Escherichia coli that cause urinary tract infections. Detailed knowledge about this interaction is important in understanding how pilicides can inhibit pilus assembly by binding to chaperones. Relaxation-edited NMR experiments were used to confirm the affinity of the pilicides for the chaperones and chemical shift mapping was used to study the pilicide-chaperone interaction surface. These studies show that at least two interaction sites are present on the chaperone surface and consequently that two different mechanisms resulting in inhibition of pilus assembly may exist.

Place, publisher, year, edition, pages
Umeå: Kemi , 2004. , 66 p.
Keyword [en]
Organic chemistry, NMR, structure calculations, peptidomimetics, desmopressin, Leu-enkephalin, chemical shift mapping, pilicides, chaperones, urinary tract infections.
Keyword [sv]
Organisk kemi
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-320ISBN: 91-7305-724-X (print)OAI: oai:DiVA.org:umu-320DiVA: diva2:143093
Public defence
2004-10-08, sal KB3B1, KBC-huset, Umeå universitet, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2004-09-20 Created: 2004-09-20 Last updated: 2010-03-08Bibliographically approved
List of papers
1. Confirmation and Receptor Activity of Desmopressin Analogues, Which Contain γ-turn mimetics or a Ψ[CH2O] isostere
Open this publication in new window or tab >>Confirmation and Receptor Activity of Desmopressin Analogues, Which Contain γ-turn mimetics or a Ψ[CH2O] isostere
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2002 In: Journal of Medicinal Chemistry, Vol. 45, no 12, 2501-2511 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-4116 (URN)
Available from: 2004-09-20 Created: 2004-09-20Bibliographically approved
2. Stereoselective Synthesis of Ψ[CH2O] Pseudodipeptids and Conformational Analysis of a Phe Ψ[CH2O]Ala Containing analogue of the Drug Desmopressin
Open this publication in new window or tab >>Stereoselective Synthesis of Ψ[CH2O] Pseudodipeptids and Conformational Analysis of a Phe Ψ[CH2O]Ala Containing analogue of the Drug Desmopressin
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2002 In: Bioorganic and Medicinal Chemistry Letters, Vol. 12, 841-844 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-4117 (URN)
Available from: 2004-09-20 Created: 2004-09-20Bibliographically approved
3. Synthesis and conformational studies of a β-turn mimetic incorporated in Leu-enkephalin
Open this publication in new window or tab >>Synthesis and conformational studies of a β-turn mimetic incorporated in Leu-enkephalin
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2004 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 69, no 10, 3500-3508 p.Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2004
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-2273 (URN)10.1021/jo0356863 (DOI)
Available from: 2007-05-03 Created: 2007-05-03 Last updated: 2017-12-14Bibliographically approved
4. Design and evaluation of Pilicides: Potential novel antibacterial agents directed against Uropathogenic Escherichia coli
Open this publication in new window or tab >>Design and evaluation of Pilicides: Potential novel antibacterial agents directed against Uropathogenic Escherichia coli
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2001 (English)In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, ChemBioChem (Online), ISSN '1439-7633', Vol. 2, no 12, 915-918 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
Wiley InterScience, 2001
Keyword
antibiotics, bioorganic chemistry, chaperone proteins, peptidomimetics
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Biorganic Chemistry
Identifiers
urn:nbn:se:umu:diva-3202 (URN)
Available from: 2003-11-28 Created: 2003-11-28 Last updated: 2017-12-14Bibliographically approved
5. NMR studies of the interactions between pilicides and periplasmic chaperones from uropathogenic E. coli
Open this publication in new window or tab >>NMR studies of the interactions between pilicides and periplasmic chaperones from uropathogenic E. coli
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Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-4120 (URN)
Available from: 2004-09-20 Created: 2004-09-20 Last updated: 2010-01-13Bibliographically approved

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