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Carbohydrate-Based Inhibitors of Pathogen Adhesion to Cell Surface Glycoconjugates

Hansen, Henrik C LU (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.



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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)
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author
opponent
  • Prof. Pinto, Mario, Canada
organization
publishing date
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
external identifiers
  • Other:LUTKDH/(TKOK-1047)/1-79/1999
ISBN
91-628-3376-6
language
English
LU publication?
yes
id
40a33292-984b-410f-af9a-27ce6c9f1663 (old id 27713)
date added to LUP
2007-06-07 15:47:34
date last changed
2016-09-19 08:45:08
@misc{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 &lt;i&gt;Escherichia coli&lt;/i&gt; (Gram negative bacterium), &lt;i&gt;Streptococcus suis&lt;/i&gt; (Gram positive bacterium), and verotoxin from &lt;i&gt;E. coli&lt;/i&gt;. 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 &lt;i&gt;S. suis&lt;/i&gt;. 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 &lt;i&gt;E. coli&lt;/i&gt; and the binding site on verotoxin from &lt;i&gt;E. coli&lt;/i&gt;, 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},
  keyword      = {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},
  pages        = {79},
  publisher    = {ARRAY(0x944bec0)},
  title        = {Carbohydrate-Based Inhibitors of Pathogen Adhesion to Cell Surface Glycoconjugates},
  year         = {1999},
}