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Potent inhibitors of uropathogenic E. coli papG adhesins; Synthesis, conformational studies and biological evaluation of galabiose derivatives and synthesis of glycosphingolipid analogues

Ohlsson, Jörgen LU (2002)
Abstract
The importance of carbohydrates in biological systems has become evident during the last fifty years. It is well known that pathogenic bacteria and viruses attach to glycoconjugates present at mammalian cell surfaces, and that this attachment is a prerequisite for the later stages of infection. Obviously, this interaction is interesting as a target for the development of novel ways to treat bacterial infections. In this thesis, the affinities of galabiose derivatives for PapG class I and II adhesins from uropathogenic E. coli have been investigated. The objective of this project was to further explore the binding event between galabiose and the adhesins, aiming at finding a high-affinity inhibitor. A high-affinity galabioside might have a... (More)
The importance of carbohydrates in biological systems has become evident during the last fifty years. It is well known that pathogenic bacteria and viruses attach to glycoconjugates present at mammalian cell surfaces, and that this attachment is a prerequisite for the later stages of infection. Obviously, this interaction is interesting as a target for the development of novel ways to treat bacterial infections. In this thesis, the affinities of galabiose derivatives for PapG class I and II adhesins from uropathogenic E. coli have been investigated. The objective of this project was to further explore the binding event between galabiose and the adhesins, aiming at finding a high-affinity inhibitor. A high-affinity galabioside might have a future as an anti-adhesive therapeutic agent targeting urinary tract infections. A large-scale synthesis of galabiose was developed and seven collections of galabiosides, totally 66 different galabiosides were synthesised and evaluated. For the class I adhesin the best known inhibitor so far was identified, being 20-30 times more potent than the natural ligand globotetraose. For the class II adhesin, associated with pyelonephritis, galabiosides with about the same affinity as the natural tetrasaccharide ligand were found. For the class II adhesin the Kd-values of the best galabiosides are still about 0.1 mM. However, this Kd-value is in the same range as the more synthetically demanding tetrasaccharide. These inhibitors represent the best inhibitors known against the class I and II PapG adhesin and the results constitute an advancement towards anti-adhesion therapeutic agents targeting urinary tract infections. In the examination of glycolipid-lectin interactions, the lipid part has often been neglected. However, during the last years, evidence has accumulated that the mode of presentation influences the recognition event. In order to mimic the binding characteristics in Nature as close as possible, the lipid part should resemble its natural counterpart. In this thesis, synthetic routes to w-mercapto and w-carboxy analogues of glycosphingolipids are described. The lipids were designed to be suitable for functionalization of gold and aminofunctionalized surfaces and to be as similar the natural glycosphingolipids as possible. (Less)
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author
supervisor
opponent
  • Prof Lowarry, Todd L., Department of Chemistry, Ohio State University, 100 West 18th Avenue, Columbus, OH 43210-1173, USA
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Organic chemistry, Organisk kemi, Glycosphingolipid analogue, PapG adhesin, Esherichia coli, Galabiose analogues, Inhibitors, Glycoconjugates
pages
107 pages
publisher
Organic Chemistry, Lund University
defense location
Chemical Center, room K:C
defense date
2002-12-06 10:15:00
external identifiers
  • other:ISRN: LUTKDH/(TKOK-1054)/1-107/(2002)
ISBN
91-628-5471-2
language
English
LU publication?
yes
additional info
Article: Jörgen Ohlsson, Göran MagnussonGalabiosyl donors; efficient synthesis from 1,2,3,4,6-penta-O-acetyl-b-D-galactopyranoseCarbohydr. Res., 2000, 329, 49-55 Article: Jörgen Ohlsson, Jana Jass, Bernt Eric Uhlin, Jan Kihlberg, Ulf J. NilssonDiscovery of potent inhibitors of PapG adhesins from uropathogenic Escherichia coli through synthesis and evaluation of galabiose derivativesChemBioChem, 2002, 3, 772-779 Article: Andreas Larsson, Jörgen Ohlsson, Karen W. Dodson, Scott J. Hultgren, Ulf J. Nilsson, Jan KihlbergQuantitative Studies of the Binding of the Class II PapG Adhesin from Uropathogenic Escherichia coli to OligosaccharidesSubmitted Article: Jörgen Ohlsson, Andreas Larsson, Jan Kihlberg, Ulf J. NilssonSynthesis of galabioside C1 and C3' derivatives and evaluation of their affinities for the PapG class II adhesin of uropathogenic Escherichia coliManuscript Article: Jörgen Ohlsson, Anders Sundin, Ulf J. NilssonConformational studies on phenyl thio-galabiosides: Remote effect on disaccharide linkage by phenyl aglycons disrupts recognition of galabiosides by a bacterial adhesinManuscript Article: Jörgen Ohlsson, Göran MagnussonA short and practical route to 3-O-benzoyl azidosphingosineCarbohydr. Res., 2001, 331, 91-94 Article: Jörgen Ohlsson, Göran Magnussonw-Mercapto Analogs of Naturally Occurring LipidsTetrahedron Lett., 1999, 40, 2011-2014 Article: Jörgen Ohlsson, Göran MagnussonAnalogues of Glycosphingolipids and Glycerolipids Suitable for Conjugation to Gold- and Amino-Functionalised SurfacesTetrahedron, 2000, 56, 9975-9984 The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Organic chemistry (S/LTH) (011001240)
id
fa03002b-d4dd-4e81-81bb-18783999a679 (old id 465256)
date added to LUP
2016-04-04 10:48:37
date last changed
2018-11-21 21:00:54
@phdthesis{fa03002b-d4dd-4e81-81bb-18783999a679,
  abstract     = {The importance of carbohydrates in biological systems has become evident during the last fifty years. It is well known that pathogenic bacteria and viruses attach to glycoconjugates present at mammalian cell surfaces, and that this attachment is a prerequisite for the later stages of infection. Obviously, this interaction is interesting as a target for the development of novel ways to treat bacterial infections. In this thesis, the affinities of galabiose derivatives for PapG class I and II adhesins from uropathogenic E. coli have been investigated. The objective of this project was to further explore the binding event between galabiose and the adhesins, aiming at finding a high-affinity inhibitor. A high-affinity galabioside might have a future as an anti-adhesive therapeutic agent targeting urinary tract infections. A large-scale synthesis of galabiose was developed and seven collections of galabiosides, totally 66 different galabiosides were synthesised and evaluated. For the class I adhesin the best known inhibitor so far was identified, being 20-30 times more potent than the natural ligand globotetraose. For the class II adhesin, associated with pyelonephritis, galabiosides with about the same affinity as the natural tetrasaccharide ligand were found. For the class II adhesin the Kd-values of the best galabiosides are still about 0.1 mM. However, this Kd-value is in the same range as the more synthetically demanding tetrasaccharide. These inhibitors represent the best inhibitors known against the class I and II PapG adhesin and the results constitute an advancement towards anti-adhesion therapeutic agents targeting urinary tract infections. In the examination of glycolipid-lectin interactions, the lipid part has often been neglected. However, during the last years, evidence has accumulated that the mode of presentation influences the recognition event. In order to mimic the binding characteristics in Nature as close as possible, the lipid part should resemble its natural counterpart. In this thesis, synthetic routes to w-mercapto and w-carboxy analogues of glycosphingolipids are described. The lipids were designed to be suitable for functionalization of gold and aminofunctionalized surfaces and to be as similar the natural glycosphingolipids as possible.},
  author       = {Ohlsson, Jörgen},
  isbn         = {91-628-5471-2},
  language     = {eng},
  publisher    = {Organic Chemistry, Lund University},
  school       = {Lund University},
  title        = {Potent inhibitors of uropathogenic E. coli papG adhesins; Synthesis, conformational studies and biological evaluation of galabiose derivatives and synthesis of glycosphingolipid analogues},
  year         = {2002},
}