The conformation of the idopyranose ring revisited: How subtle O-substituent induced changes can be deduced from vicinal 1H-NMR coupling constants

Haasnoot, C. A. G.; Gelder, René de; Kooijman, Huub; Kellenbach, Edwin

doi:10.1016/j.carres.2020.108052

Cited by 14 publications

(30 citation statements)

References 89 publications

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“…Unlike group C, chemokines CCL5 and CCL2 showed exclusive strong binding to high-sulfated HS mimetics, no binding to non-sulfated mimetics, and weak binding with a mono-sulfated ligand. Among high-sulfate ligands, I-23 and I-45 revealed strong binding to group D chemokines, indicating that sulfation code, even number of IdoA units, and absolute 1 C 4 -IdoA conformation are critical for CCL2 and CCL5 activation. Interestingly, 4- O -sulfation enhances the population of the 1 C 4 geometry, and this conformer becomes exclusive upon additional 2- O -sulfation.…”

Section: Results and Discussionsupporting

confidence: 91%

Heparan Sulfate Mimetics Differentially Affect Homologous Chemokines and Attenuate Cancer Development

et al. 2021

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Achieving selective inhibition of chemokine activity by structurally well-defined heparan sulfate (HS) or HS mimetic molecules can provide important insights into their roles in individual physiological and pathological cellular processes. Here, we report a novel tailor-made HS mimetic, which furnishes an exclusive iduronic acid (IdoA) scaffold with different sulfation patterns and oligosaccharide chain lengths as potential ligands to target chemokines. Notably, highly sulfated-IdoA tetrasaccharide (I-45) exhibited strong binding to CCL2 chemokine thereby blocking CCL2/CCR2-mediated in vitro cancer cell invasion and metastasis. Taken together, IdoA-based HS mimetics offer an alternative HS substrate to generate selective and efficient inhibitors for chemokines and pave the way to a wide range of new therapeutic applications in cancer biology and immunology.

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Section: Results and Discussionsupporting

confidence: 91%

Heparan Sulfate Mimetics Differentially Affect Homologous Chemokines and Attenuate Cancer Development

et al. 2021

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“…In the three different chemically synthesized heparin pentasaccharides, the pentasaccharide had anticoagulant activity only when IdoA was in 2 S 0 (Das et al, 2001). Therefore, the proportion of 2 S 0 of IdoA in the heparin pentasaccharide sequence was one of the factors affecting the binding rate, which was affected by the degree of sulfation of glucosamine on both sides and its own 2-O-SO 3 (Haasnoot et al, 2020). Although the absence of 2-O-SO 3 in IdoA had no significant effect on the binding conformation, it resulted in a decrease in the proportion of free state 2 S 0 and a twofold decrease in affinity (Stancanelli et al, 2018).…”

Section: Heparin/heparan Sulfatementioning

confidence: 99%

“…This gives these three different types of GAGs more flexible and various protein binding activities. This balance is affected by chain length, the degree of sulfation of adjacent monosaccharides, and its own 2-O sulfation (Haasnoot et al, 2020). When interacting with proteins, the conformational balance of IdoA will be tilted, such as binding to fibroblast growth factor-2 (FGF2), fibroblast growth factor-2 receptor (FGF2R), and eosinophil cationic protein (Ecp) (Hricovíni et al, 2002;García-Mayoral et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

NMR Characterization of the Interactions Between Glycosaminoglycans and Proteins

Jin

2021

Front. Mol. Biosci.

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Glycosaminoglycans (GAGs) constitute a considerable fraction of the glycoconjugates found on cellular membranes and in the extracellular matrix of virtually all mammalian tissues. The essential role of GAG-protein interactions in the regulation of physiological processes has been recognized for decades. However, the underlying molecular basis of these interactions has only emerged since 1990s. The binding specificity of GAGs is encoded in their primary structures, but ultimately depends on how their functional groups are presented to a protein in the three-dimensional space. This review focuses on the application of NMR spectroscopy on the characterization of the GAG-protein interactions. Examples of interpretation of the complex mechanism and characterization of structural motifs involved in the GAG-protein interactions are given. Selected families of GAG-binding proteins investigated using NMR are also described.

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“…The population combination that provides the best fit is assumed to be the actual conformational distribution in solution. However, this approach suffers from some intrinsic caveats, since the intrinsic mobility of the 2 S 0 conformer makes it very difficult to estimate the exact J and NOE data . Nevertheless, NOE-derived distances between H2 and H5 within the IdoA ring have been traditionally used as an estimation of the relative population of the 2 S 0 -form .…”

Section: Results and Discussionmentioning

confidence: 99%

“…However, this approach suffers from some intrinsic caveats, since the intrinsic mobility of the 2 S 0 conformer makes it very difficult to estimate the exact J and NOE data. 34 Nevertheless, NOE-derived distances between H2 and H5 within the IdoA ring have been traditionally used as an estimation of the relative population of the 2 S 0 -form. 35 In fact, the existence of short distance between H2 and H5 protons, ca.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Sulfation Code and Conformational Plasticity of l-Iduronic Acid Homo-Oligosaccharides Mimic the Biological Functions of Heparan Sulfate

et al. 2021

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Recently, the activity of heparan sulfate (HS) has led to the discovery of many drug candidates that have the potential to impact both medical science and human health. However, structural diversity and synthetic challenges impede the progress of HS research. Here, we report a library of novel l-iduronic acid (IdoA)-based HS mimics that are highly tunable in conformation plasticity and sulfation patterns to produce many of the functions of native HS oligosaccharides. The NMR analysis of HS mimics confirmed that 4-O-sulfation enhances the population of the 1C4 geometry. Interestingly, the 1C4 conformer becomes exclusive upon additional 2-O-sulfation. HS mimic microarray binding studies with different growth factors showed that selectivity and avidity are greatly modulated by the oligosaccharide length, sulfation code, and IdoA conformation. Particularly, we have identified 4-O-sulfated IdoA disaccharide (I-21) as a potential ligand for vascular endothelial growth factor (VEGF165), which in a multivalent display modulated endothelial cell proliferation, migration, and angiogenesis. Overall, these results encourage the consideration of HS mimics for therapeutic applications.

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The conformation of the idopyranose ring revisited: How subtle O-substituent induced changes can be deduced from vicinal 1H-NMR coupling constants

Cited by 14 publications

References 89 publications

Heparan Sulfate Mimetics Differentially Affect Homologous Chemokines and Attenuate Cancer Development

Heparan Sulfate Mimetics Differentially Affect Homologous Chemokines and Attenuate Cancer Development

NMR Characterization of the Interactions Between Glycosaminoglycans and Proteins

Sulfation Code and Conformational Plasticity of l-Iduronic Acid Homo-Oligosaccharides Mimic the Biological Functions of Heparan Sulfate

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