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Synthesis of and molecular dynamics simulations on a tetrasaccharide corresponding to the repeating unit of the capsular polysaccharide from Salmonella enteritidis
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Stockholm University, Faculty of Science, Department of Organic Chemistry.
Stockholm University, Faculty of Science, Department of Organic Chemistry.
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2009 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 7, no 8, 1612-1618 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2009. Vol. 7, no 8, 1612-1618 p.
Identifiers
URN: urn:nbn:se:su:diva-28937DOI: 10.1039/b823428kISI: 000265195100014OAI: oai:DiVA.org:su-28937DiVA: diva2:227994
Available from: 2009-07-22 Created: 2009-07-22 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Synthesis of Bacterial Oligosaccharides from N. meningitidis and Mechanistic Details of Stereoselective Glycosylations Using a Novel Bicyclic Donor
Open this publication in new window or tab >>Synthesis of Bacterial Oligosaccharides from N. meningitidis and Mechanistic Details of Stereoselective Glycosylations Using a Novel Bicyclic Donor
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis includes two parts. The first part, comprising Chapters 3, 4 and 5, describes the synthesis of bacterial oligosaccharides. In Chapters 3 and 4, the synthesis of branched and phosphorylated oligosaccharide structures corresponding to inner core epitopes of the lipopolysaccharide (LPS) of the Gram-negative bacteria N. meningitidis are discussed. A series of different spacer-equipped, phosphorylated and non-phosphorylated, glycosides has been synthesized as a part of a program involving development of a glycoconjugate-based vaccine against meningitis. Chapter 5 describes the synthesis of a tetrasaccharide corresponding to the repeating unit of the extracellular capsular polysaccharide (CPS) found in S. enteritidis. A short and efficient synthetic route to a trisaccharide acceptor corresponding to the common Gal-Man-Rha backbone found in several Salmonella O-antigen is presented. Further more, the synthesis of a novel tyveloside thioglycoside and the final glycosylation to assemble the complete target tetrasaccharide is reported.

The second part, Chapters 6 and 7, describes the development of a novel type of glycosyl donor, a 2N,3O-oxazolidinone protected bicyclic thioglycoside. This donor can be used in stereoselective glycosylations where, by tuning the reaction conditions, either complete α- or β-selectivity can be obtained from the same donor/acceptor system. A mechanistic explanation for this behaviour, involving initial formation of the β-anomer followed by a AgOTf-catalyzed in situ endocyclic anomerization to yield the more stable corresponding α-anomer, has been established. The suggested mechanism was supported by a series of NMR-experiments. Finally, in Chapter 7, the synthesis and use of a galacto-configured 2N,3O-oxazolidinone donor for the synthesis of a serine 2-acetamido 2-deoxy galactoside, a versatile building block for the synthesis of mucin O-glycan core structures, is discussed.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University, 2009. 76 p.
Keyword
oligosaccharide synthesis, heptose, thioglycoside, glycosylation, Neisseria meningitidis, 2, 3-oxazolidinone
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-29568 (URN)978-91-7155-919-7 (ISBN)
Public defence
2009-10-09, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
At the time of the doctoral defence, the following papers we unpublished and had a status as follows: Paper 1: Manuscript. Paper 5: ManuscriptAvailable from: 2009-09-18 Created: 2009-09-06 Last updated: 2009-09-08Bibliographically approved
2. Structure, dynamics and interactions of biomolecules: Investigations by NMR spectroscopy and computational methods
Open this publication in new window or tab >>Structure, dynamics and interactions of biomolecules: Investigations by NMR spectroscopy and computational methods
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this thesis, the structure, dynamics and interactions of proteins and carbohydrates are investigated using mainly NMR spectroscopy and computer simulations.

Oligosaccharides representing a Salmonella O-antigen have been synthesized and their dynamic behavior and interaction with the bacteriophage P22 tail-spike protein have been studied by NMR spectroscopy, MD and docking simulations. A binding mechanism between the protein and the O-antigen has been proposed.

Transient hydrogen bonds have been defined and examined in an E. coli polysaccharide and in a pentasaccharide representing the repeating unit, using MD simulation and NMR spectroscopy.

Conformational dynamics of a trisaccharide representing the repeating unit of an A. salmonicida O-antigen have been investigated by MD simulations. The simulation together with relaxation matrix calculations reveals a conformational exchange on a ns timescale and explains an unusual NOE.

A fragment-based screening for inhibitors of the glycosyltransferase GTB acceptor site has been performed using NMR spectroscopy and SPR. IC50 values of the binding fragments are reported. Complex structures of the fragments and GTB have been proposed using docking simulations.

A fragment-based screening for inhibitors of the WaaG glycosyltransferase donor site has been performed using NMR spectroscopy and three compounds were selected. Structures of the WaaG-fragment complexes have been suggested from docking simulations. Binding of natural substrates and activity has also been investigated by NMR spectroscopy. MD simulations have been carried out on WaaG with and without bound donor substrate. The simulation revealed a conformational change upon substrate binding.

Interactions between HEWL and carbohydrate ligands have been investigated, using a combination of weak affinity chromatography, NMR spectroscopy and computer simulations. KDs of the ligands have been presented as well as the solution structures of two HEWL-disaccharide complexes.

Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University, 2009. 82 p.
Keyword
NMR spectroscopy, MD simulation, carbohydrate synthesis, protein-ligand interaction, glycosyltransferase
National Category
Chemical Sciences
Research subject
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-30120 (URN)978-91-7155-953-1 (ISBN)
Public defence
2009-11-13, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Submitted. Paper 4: Submitted. Paper 5: In progress. Paper 6: In progress. Paper 7: Manuscript.Available from: 2009-10-22 Created: 2009-10-04 Last updated: 2011-11-23Bibliographically approved

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