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Determining the Affinity and Kinetics of Small Molecule Inhibitors of Galectin-1 Using Surface Plasmon Resonance

Kim, Henry ; Kretz, Louis ; Ronin, Céline ; Starck, Christina ; Roper, James A. ; Kahl-Knutson, Barbro LU ; Peterson, Kristoffer LU ; Leffler, Hakon LU ; Nilsson, Ulf J. LU and Pedersen, Anders , et al. (2024) In International Journal of Molecular Sciences 25(12).
Abstract

The beta-galactoside-binding mammalian lectin galectin-1 can bind, via its carbohydrate recognition domain (CRD), to various cell surface glycoproteins and has been implicated in a range of cancers. As a consequence of binding to sugar residues on cell surface receptors, it has been shown to have a pleiotropic effect across many cell types and mechanisms, resulting in immune system modulation and cancer progression. As a result, it has started to become a therapeutic target for both small and large molecules. In previous studies, we used fluorescence polarization (FP) assays to determine KD values to screen and triage small molecule glycomimetics that bind to the galectin-1 CRD. In this study, surface plasmon resonance (SPR)... (More)

The beta-galactoside-binding mammalian lectin galectin-1 can bind, via its carbohydrate recognition domain (CRD), to various cell surface glycoproteins and has been implicated in a range of cancers. As a consequence of binding to sugar residues on cell surface receptors, it has been shown to have a pleiotropic effect across many cell types and mechanisms, resulting in immune system modulation and cancer progression. As a result, it has started to become a therapeutic target for both small and large molecules. In previous studies, we used fluorescence polarization (FP) assays to determine KD values to screen and triage small molecule glycomimetics that bind to the galectin-1 CRD. In this study, surface plasmon resonance (SPR) was used to compare human and mouse galectin-1 affinity measures with FP, as SPR has not been applied for compound screening against this galectin. Binding affinities for a selection of mono- and di-saccharides covering a 1000-fold range correlated well between FP and SPR assay formats for both human and mouse galectin-1. It was shown that slower dissociation drove the increased affinity at human galectin-1, whilst faster association was responsible for the effects in mouse galectin-1. This study demonstrates that SPR is a sound alternative to FP for early drug discovery screening and determining affinity estimates. Consequently, it also allows association and dissociation constants to be measured in a high-throughput manner for small molecule galectin-1 inhibitors.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Galectin 1/metabolism, Surface Plasmon Resonance/methods, Humans, Animals, Mice, Kinetics, Protein Binding, Small Molecule Libraries/pharmacology, Fluorescence Polarization/methods
in
International Journal of Molecular Sciences
volume
25
issue
12
article number
6704
pages
10 pages
publisher
MDPI AG
external identifiers
  • pmid:38928409
  • scopus:85197105409
ISSN
1422-0067
DOI
10.3390/ijms25126704
language
English
LU publication?
yes
id
ed96fba4-09ea-4d08-8941-2e26a6408927
date added to LUP
2024-06-27 17:58:02
date last changed
2025-06-18 19:27:58
@article{ed96fba4-09ea-4d08-8941-2e26a6408927,
  abstract     = {{<p>The beta-galactoside-binding mammalian lectin galectin-1 can bind, via its carbohydrate recognition domain (CRD), to various cell surface glycoproteins and has been implicated in a range of cancers. As a consequence of binding to sugar residues on cell surface receptors, it has been shown to have a pleiotropic effect across many cell types and mechanisms, resulting in immune system modulation and cancer progression. As a result, it has started to become a therapeutic target for both small and large molecules. In previous studies, we used fluorescence polarization (FP) assays to determine K<sub>D</sub> values to screen and triage small molecule glycomimetics that bind to the galectin-1 CRD. In this study, surface plasmon resonance (SPR) was used to compare human and mouse galectin-1 affinity measures with FP, as SPR has not been applied for compound screening against this galectin. Binding affinities for a selection of mono- and di-saccharides covering a 1000-fold range correlated well between FP and SPR assay formats for both human and mouse galectin-1. It was shown that slower dissociation drove the increased affinity at human galectin-1, whilst faster association was responsible for the effects in mouse galectin-1. This study demonstrates that SPR is a sound alternative to FP for early drug discovery screening and determining affinity estimates. Consequently, it also allows association and dissociation constants to be measured in a high-throughput manner for small molecule galectin-1 inhibitors.</p>}},
  author       = {{Kim, Henry and Kretz, Louis and Ronin, Céline and Starck, Christina and Roper, James A. and Kahl-Knutson, Barbro and Peterson, Kristoffer and Leffler, Hakon and Nilsson, Ulf J. and Pedersen, Anders and Zetterberg, Fredrik R. and Slack, Robert J.}},
  issn         = {{1422-0067}},
  keywords     = {{Galectin 1/metabolism; Surface Plasmon Resonance/methods; Humans; Animals; Mice; Kinetics; Protein Binding; Small Molecule Libraries/pharmacology; Fluorescence Polarization/methods}},
  language     = {{eng}},
  number       = {{12}},
  publisher    = {{MDPI AG}},
  series       = {{International Journal of Molecular Sciences}},
  title        = {{Determining the Affinity and Kinetics of Small Molecule Inhibitors of Galectin-1 Using Surface Plasmon Resonance}},
  url          = {{http://dx.doi.org/10.3390/ijms25126704}},
  doi          = {{10.3390/ijms25126704}},
  volume       = {{25}},
  year         = {{2024}},
}