Carbohydrate-Based Inhibitors of Pathogen Adhesion to Cell Surface Glycoconjugates
(1999)- Abstract
- The fact that a growing number of pathogens develop resistance against traditional treatment is a growing medical problem. Infections, which until now have been harmless, might turn into life threatening diseases. These problems have led to an intensified search for alternative treatments. Analogs of cell surface glycoconjugates are an alternative. Ideally they prevent the adhesion of the pathogen, the first stage in many infectious processes. One problem in the development of carbohydrate-based drugs is the normally weak (mM) interactions between cell surface glycoconjugates and their protein receptors. Stronger inhibitors of the recognition event are a prerequisite for the development of drug candidates.
We have... (More) - The fact that a growing number of pathogens develop resistance against traditional treatment is a growing medical problem. Infections, which until now have been harmless, might turn into life threatening diseases. These problems have led to an intensified search for alternative treatments. Analogs of cell surface glycoconjugates are an alternative. Ideally they prevent the adhesion of the pathogen, the first stage in many infectious processes. One problem in the development of carbohydrate-based drugs is the normally weak (mM) interactions between cell surface glycoconjugates and their protein receptors. Stronger inhibitors of the recognition event are a prerequisite for the development of drug candidates.
We have synthesized and investigated analogs of galabiose (Gala1-4Galb) and globotriose (Gala1-4Galb1-4Glcb), as inhibitors of cell surface adhesion processes. The Gala1-4Gal epitope is recognized by uropathogenic <i>Escherichia coli</i> (Gram negative bacterium), <i>Streptococcus suis</i> (Gram positive bacterium), and verotoxin from <i>E. coli</i>. The work has been focused on two major subjects: 1) Synthetic oligovalent inhibitors. In nature the low affinity binding between individual glycoconjugates and protein is compensated by multivalent adhesion. 2) Amino-deoxy analogs of natural ligands.
In the present study we have synthesized mono- to tetravalent dendritic galabiosides and globotriosides, by coupling of galabiose and globotriose derivatives to carrier molecules having mono- to tetrameric functionalities. A number of these analogs were tested as inhibitors of hemagglutination by <i>S. suis</i>. The di- to tetravalent galabiosides were several hundred times more efficient than the monomeric analog, resulting in complete inhibition at low nanomolar concentrations.
Based on models of the binding site on PapGJ96 from uropathogenic <i>E. coli</i> and the binding site on verotoxin from <i>E. coli</i>, we have selected and synthesized a number of amino-deoxy- galabiosides and ?globotriosides. The 6-, 2'-, 4', and 6'-amino-deoxy galabiosides were synthesized as 2-(trimethylsilyl)ethyl glycosides, and the 6'-, 2''-, 4''-, and 6''-amino-deoxy globotriosides were synthesized as 2-(trimethylsilyl)ethyl glycosides and as adamantyl ceramide analogs. It was shown, by NMR and MM3 calculations, that the amino-deoxy analogs had conformations very similar to the natural glycosides. The 6- and 2'-amino-deoxy galabiosides and a 6-carboxy analog were tested as inhibitors of PapGJ96 adhesion in a compeptitive ELISA. The results supported the proposed model for binding site. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/27713
- author
- Hansen, Henrik C LU
- supervisor
- opponent
-
- Prof. Pinto, Mario, Canada
- organization
- publishing date
- 1999
- type
- Thesis
- publication status
- published
- subject
- keywords
- Galabiose analogs, Globotriose analogs, Escherichia coli, verotoxin, PapG adhesion, Streptococcus suis, Dendrimers, Multivalency, Amino-deoxy analogs, Organic chemistry, Inhibitor, Ceramide analogs, Glycoconjugates, Organisk kemi
- pages
- 79 pages
- publisher
- Organic Chemistry, Lund University
- defense location
- Chemical Center KC
- defense date
- 1999-04-23 13:15:00
- external identifiers
-
- other:LUTKDH/(TKOK-1047)/1-79/1999
- ISBN
- 91-628-3376-6
- language
- English
- LU publication?
- yes
- additional info
- 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
- 40a33292-984b-410f-af9a-27ce6c9f1663 (old id 27713)
- date added to LUP
- 2016-04-04 11:08:53
- date last changed
- 2018-11-21 21:02:57
@phdthesis{40a33292-984b-410f-af9a-27ce6c9f1663,
abstract = {{The fact that a growing number of pathogens develop resistance against traditional treatment is a growing medical problem. Infections, which until now have been harmless, might turn into life threatening diseases. These problems have led to an intensified search for alternative treatments. Analogs of cell surface glycoconjugates are an alternative. Ideally they prevent the adhesion of the pathogen, the first stage in many infectious processes. One problem in the development of carbohydrate-based drugs is the normally weak (mM) interactions between cell surface glycoconjugates and their protein receptors. Stronger inhibitors of the recognition event are a prerequisite for the development of drug candidates.<br/><br>
<br/><br>
We have synthesized and investigated analogs of galabiose (Gala1-4Galb) and globotriose (Gala1-4Galb1-4Glcb), as inhibitors of cell surface adhesion processes. The Gala1-4Gal epitope is recognized by uropathogenic <i>Escherichia coli</i> (Gram negative bacterium), <i>Streptococcus suis</i> (Gram positive bacterium), and verotoxin from <i>E. coli</i>. The work has been focused on two major subjects: 1) Synthetic oligovalent inhibitors. In nature the low affinity binding between individual glycoconjugates and protein is compensated by multivalent adhesion. 2) Amino-deoxy analogs of natural ligands.<br/><br>
<br/><br>
In the present study we have synthesized mono- to tetravalent dendritic galabiosides and globotriosides, by coupling of galabiose and globotriose derivatives to carrier molecules having mono- to tetrameric functionalities. A number of these analogs were tested as inhibitors of hemagglutination by <i>S. suis</i>. The di- to tetravalent galabiosides were several hundred times more efficient than the monomeric analog, resulting in complete inhibition at low nanomolar concentrations.<br/><br>
<br/><br>
Based on models of the binding site on PapGJ96 from uropathogenic <i>E. coli</i> and the binding site on verotoxin from <i>E. coli</i>, we have selected and synthesized a number of amino-deoxy- galabiosides and ?globotriosides. The 6-, 2'-, 4', and 6'-amino-deoxy galabiosides were synthesized as 2-(trimethylsilyl)ethyl glycosides, and the 6'-, 2''-, 4''-, and 6''-amino-deoxy globotriosides were synthesized as 2-(trimethylsilyl)ethyl glycosides and as adamantyl ceramide analogs. It was shown, by NMR and MM3 calculations, that the amino-deoxy analogs had conformations very similar to the natural glycosides. The 6- and 2'-amino-deoxy galabiosides and a 6-carboxy analog were tested as inhibitors of PapGJ96 adhesion in a compeptitive ELISA. The results supported the proposed model for binding site.}},
author = {{Hansen, Henrik C}},
isbn = {{91-628-3376-6}},
keywords = {{Galabiose analogs; Globotriose analogs; Escherichia coli; verotoxin; PapG adhesion; Streptococcus suis; Dendrimers; Multivalency; Amino-deoxy analogs; Organic chemistry; Inhibitor; Ceramide analogs; Glycoconjugates; Organisk kemi}},
language = {{eng}},
publisher = {{Organic Chemistry, Lund University}},
school = {{Lund University}},
title = {{Carbohydrate-Based Inhibitors of Pathogen Adhesion to Cell Surface Glycoconjugates}},
year = {{1999}},
}