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

Författare

Summary, in English

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.

Publiceringsår

2024-02-26

Språk

Engelska

Dokumenttyp

Doktorsavhandling

Förlag

MediaTryck Lund

Ämne

  • Medicinal Chemistry

Nyckelord

  • Galectins
  • structure activity relation

Status

Published

Handledare

  • Ulf Nilsson
  • Tihomir Tomašič
  • Richard Escobar Johnsson
  • Björn Walse

ISBN/ISSN/Övrigt

  • ISBN: 978-91-8096-023-6
  • ISBN: 978-91-8096-022-9

Försvarsdatum

22 mars 2024

Försvarstid

14:00

Försvarsplats

Lecture Hall P1, Faculty of Pharmacy, University of Ljubljana, Join via zoom: https://uni-lj-si.zoom.us/j/95201791655

Opponent

  • Barbera Richichi (Associate Professor)