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Small-Molecule Galectin Ligands : Structure-Based Optimisation of Affinity and Selectivity

Van Klaveren, Sjors LU (2024)
Abstract
In the body, all cell surfaces are covered with glycans, and many regulatory components have
carbohydrates attached to them, which can aid in their function. Galectins are a family of proteins which
can bind to specific glycans and oligosaccharides and cross-link them to influence a wide range of cellular
processes. The members of the galectin family are structurally similar and can be involved in the same
processes. Inside the cell, galectins have been observed assisting in the detection of exposed glycans
on damaged intracellular vesicles, initiating autophagy which helps to clear out damaged cells and
bacterial infections. Some galectins have a role in promoting angiogenesis and lymphangiogenesis. This
is... (More)
In the body, all cell surfaces are covered with glycans, and many regulatory components have
carbohydrates attached to them, which can aid in their function. Galectins are a family of proteins which
can bind to specific glycans and oligosaccharides and cross-link them to influence a wide range of cellular
processes. The members of the galectin family are structurally similar and can be involved in the same
processes. Inside the cell, galectins have been observed assisting in the detection of exposed glycans
on damaged intracellular vesicles, initiating autophagy which helps to clear out damaged cells and
bacterial infections. Some galectins have a role in promoting angiogenesis and lymphangiogenesis. This
is associated with the repair of damaged tissue and with the growth of tumours. Studies have also
implicated galectins in autoimmune disorders and neurodegenerative diseases.
The research in this doctoral dissertation focused on the discovery and development of selective, highaffinity
ligands for several galectins, with a special focus on galectin-8. Several structurally diverse
libraries of compounds were synthesised as part of ligand-based and structure-based approaches. From
these libraries, several novel hits for galectin-1, -3, and -8N were discovered and structure–affinity
relationships were identified. These hits were optimised to produce galectin ligands with sub-micromolar
affinities and analogues with almost complete selectivity for galectin-8N over all other tested galectins.
Such highly selective compounds may help to study the biological roles of galectins and the pathologies
in which they are involved. This may also, in turn, lead to galectin-8N inhibitors with a pharmaceutical
potential. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Associate Professor Richichi, Barbera, Department of Chemistry, University of Florence
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Galectins, structure activity relation
pages
128 pages
publisher
MediaTryck Lund
defense location
Lecture Hall P1, Faculty of Pharmacy, University of Ljubljana, Join via zoom: https://uni-lj-si.zoom.us/j/95201791655
defense date
2024-03-22 14:00:00
ISBN
978-91-8096-022-9
978-91-8096-023-6
language
English
LU publication?
yes
id
6a21af75-81b9-4b8f-a49f-169ad67ef13d
date added to LUP
2024-02-26 23:09:56
date last changed
2024-02-28 11:19:56
@phdthesis{6a21af75-81b9-4b8f-a49f-169ad67ef13d,
  abstract     = {{In the body, all cell surfaces are covered with glycans, and many regulatory components have<br/>carbohydrates attached to them, which can aid in their function. Galectins are a family of proteins which<br/>can bind to specific glycans and oligosaccharides and cross-link them to influence a wide range of cellular<br/>processes. The members of the galectin family are structurally similar and can be involved in the same<br/>processes. Inside the cell, galectins have been observed assisting in the detection of exposed glycans<br/>on damaged intracellular vesicles, initiating autophagy which helps to clear out damaged cells and<br/>bacterial infections. Some galectins have a role in promoting angiogenesis and lymphangiogenesis. This<br/>is associated with the repair of damaged tissue and with the growth of tumours. Studies have also<br/>implicated galectins in autoimmune disorders and neurodegenerative diseases.<br/>The research in this doctoral dissertation focused on the discovery and development of selective, highaffinity<br/>ligands for several galectins, with a special focus on galectin-8. Several structurally diverse<br/>libraries of compounds were synthesised as part of ligand-based and structure-based approaches. From<br/>these libraries, several novel hits for galectin-1, -3, and -8N were discovered and structure–affinity<br/>relationships were identified. These hits were optimised to produce galectin ligands with sub-micromolar<br/>affinities and analogues with almost complete selectivity for galectin-8N over all other tested galectins.<br/>Such highly selective compounds may help to study the biological roles of galectins and the pathologies<br/>in which they are involved. This may also, in turn, lead to galectin-8N inhibitors with a pharmaceutical<br/>potential.}},
  author       = {{Van Klaveren, Sjors}},
  isbn         = {{978-91-8096-022-9}},
  keywords     = {{Galectins; structure activity relation}},
  language     = {{eng}},
  month        = {{02}},
  publisher    = {{MediaTryck Lund}},
  school       = {{Lund University}},
  title        = {{Small-Molecule Galectin Ligands : Structure-Based Optimisation of Affinity and Selectivity}},
  url          = {{https://lup.lub.lu.se/search/files/172810441/Sjors_van_Klaveren_-_WEB.pdf}},
  year         = {{2024}},
}