Low-Molecular Weight Inhibitors of Galectins
(2012) Symposium on Galectin Function and 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:
https://lup.lub.lu.se/record/3768147
- author
- Leffler, Hakon LU and Nilsson, Ulf LU
- organization
- publishing date
- 2012
- type
- Chapter in Book/Report/Conference proceeding
- publication status
- published
- subject
- host publication
- Galectins and Disease Implications for Targeted Therapeutics
- volume
- 1115
- pages
- 47 - 59
- publisher
- American Institute of Physics (AIP)
- conference name
- Symposium on Galectin Function and Therapeutics
- conference dates
- 2012-09-17 - 2012-09-19
- 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
- 2016-04-01 14:55:41
- date last changed
- 2022-01-28 03:10:06
@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 (AIP)}},
title = {{Low-Molecular Weight Inhibitors of Galectins}},
url = {{http://dx.doi.org/10.1021/bk-2012-1115.ch002}},
doi = {{10.1021/bk-2012-1115.ch002}},
volume = {{1115}},
year = {{2012}},
}