Advanced

Low-Molecular Weight Inhibitors of Galectins

Leffler, Hakon LU and Nilsson, Ulf LU (2012) Symposium on Galectin Function and Therapeutics In Galectins and Disease Implications for Targeted Therapeutics 1115. p.47-59
Abstract
The galectins are known to be able to recognize and cross-link beta-D-galactopyranoside-containing glycoconjugates as a result of presenting multiple binding sites. This review summarizes efforts in our group for the last ten years towards low-molecular weight chemically modified carbohydrate derivatives. In addition to providing an avenue for improved affinity and galectin-selectivity, we have focused on the chemical synthesis of low-molecular weight inhibitors, since synthetic derivatives offer opportunities to design more "drug-like" in order to circumvent drawbacks typically associated with natural oligosaccharides and fragments, such as low affinity (high mu M to mM for galectins), limited chemical and metabolic stability, and high... (More)
The galectins are known to be able to recognize and cross-link beta-D-galactopyranoside-containing glycoconjugates as a result of presenting multiple binding sites. This review summarizes efforts in our group for the last ten years towards low-molecular weight chemically modified carbohydrate derivatives. In addition to providing an avenue for improved affinity and galectin-selectivity, we have focused on the chemical synthesis of low-molecular weight inhibitors, since synthetic derivatives offer opportunities to design more "drug-like" in order to circumvent drawbacks typically associated with natural oligosaccharides and fragments, such as low affinity (high mu M to mM for galectins), limited chemical and metabolic stability, and high polarity leading to low bioavailability and rapid clearance. The examples described in the review provide evidence that it is possible to improve both affinity and selectivity of low-molecular weight compounds for galectins by chemically modifying galactose (and other monosaccharides) with non-carbohydrate structural elements targeting ligand sub-sites flanking the core galactose-binding sub-site C. Indeed, inhibitors have been made that possess both low-nM affinities for galectins and that show potent in vivo efficacy. Hence, promising low-molecular weight galectin-targeting lead structures have been identified, although it remains to investigate and optimize ADME and toxicology aspects of these compounds in order to fully reach the status of identifying clinical candidates. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Chapter in Book/Report/Conference proceeding
publication status
published
subject
in
Galectins and Disease Implications for Targeted Therapeutics
volume
1115
pages
47 - 59
publisher
American Institute of Physics
conference name
Symposium on Galectin Function and Therapeutics
external identifiers
  • wos:000316091100002
  • scopus:84905226184
ISSN
0097-6156
DOI
10.1021/bk-2012-1115.ch002
language
English
LU publication?
yes
id
217734c8-7284-40aa-91ea-a03ce718a19b (old id 3768147)
date added to LUP
2013-05-22 14:23:50
date last changed
2017-04-16 04:01:59
@inproceedings{217734c8-7284-40aa-91ea-a03ce718a19b,
  abstract     = {The galectins are known to be able to recognize and cross-link beta-D-galactopyranoside-containing glycoconjugates as a result of presenting multiple binding sites. This review summarizes efforts in our group for the last ten years towards low-molecular weight chemically modified carbohydrate derivatives. In addition to providing an avenue for improved affinity and galectin-selectivity, we have focused on the chemical synthesis of low-molecular weight inhibitors, since synthetic derivatives offer opportunities to design more "drug-like" in order to circumvent drawbacks typically associated with natural oligosaccharides and fragments, such as low affinity (high mu M to mM for galectins), limited chemical and metabolic stability, and high polarity leading to low bioavailability and rapid clearance. The examples described in the review provide evidence that it is possible to improve both affinity and selectivity of low-molecular weight compounds for galectins by chemically modifying galactose (and other monosaccharides) with non-carbohydrate structural elements targeting ligand sub-sites flanking the core galactose-binding sub-site C. Indeed, inhibitors have been made that possess both low-nM affinities for galectins and that show potent in vivo efficacy. Hence, promising low-molecular weight galectin-targeting lead structures have been identified, although it remains to investigate and optimize ADME and toxicology aspects of these compounds in order to fully reach the status of identifying clinical candidates.},
  author       = {Leffler, Hakon and Nilsson, Ulf},
  booktitle    = {Galectins and Disease Implications for Targeted Therapeutics},
  issn         = {0097-6156},
  language     = {eng},
  pages        = {47--59},
  publisher    = {American Institute of Physics},
  title        = {Low-Molecular Weight Inhibitors of Galectins},
  url          = {http://dx.doi.org/10.1021/bk-2012-1115.ch002},
  volume       = {1115},
  year         = {2012},
}