Examination of the Biological Role of the α(2→6)-Linked Sialic Acid in Gangliosides Binding to the Myelin-Associated Glycoprotein (MAG)

Schwardt, Oliver; Gäthje, Heiko; Vedani, Angelo; Mesch, Stefanie; Gao, Gan‐Pan; Spreafico, Morena; Orelli, Johannes von; Kelm, Sørge; Ernst, Beat

doi:10.1021/jm801058n

Cited by 23 publications

(33 citation statements)

References 78 publications

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“…In addition, the carboxylates of the two Neu5Ac moieties are involved in salt bridges and the C(9)-OH of the α(2-3)-linked Neu5Ac is forming a relevant hydrogen bond. [25] A verification of these findings by docking studies to a homology model of MAG [29,30] revealed the corresponding amino acids forming the binding site (Figs 3 and 6). Based on this information, a rational approach for the design of MAG antagonists was envisaged.…”

Section: Design Of Glycomimeticsmentioning

confidence: 64%

“…Combined with the most successful modification of the 9-position of the α(2-3)-linked Neu5Ac (Scheme 2) antagonist 29 with low micromolar affinity could be identified (Scheme 4). [30] …”

Section: Lipophilic and Hydrophilic Replacements Of The α(2-6)-linkedmentioning

confidence: 99%

“…For the evaluation of the binding properties of these new MAG antagonists two assay formats were applied; a fluorescent hapten binding assay [43] and a surface plasmon resonance based biosensor (Biacore) experiment [30,41] (Fig. 5).…”

Section: Determination Of Affinity For Magmentioning

confidence: 99%

“…4.ReplacementoftheGalb(1-3)GalNAc coreof4byabiphenyl(5)leadstoonly marginalchangesoftherequiredspatial orientationofthecarboxylateoftheα(2-6)-linkedNeu5Ac,butresultsinafour-fold reductioninaffinity. [36] [38] 10 [38] Scheme1.a)4-Bromophenol,BnNEt 3 Br, aq.NaOH/DCM,40°C,2.5h,56%;b) bis(picanolato)diborane,KOAc,PdCl 2 (dppf), dppf,dioxane,MW120°C,45min,85%;c) 3-iodophenol,BnNEt 3 29 [30] c)…”

Section: Determination Of Affinity For Magmentioning

confidence: 99%

“…24 [30] target compartment of an in vivo application. Furthermore, the logD octanol/water value of -0.26 is beneficial for an intrathecal application, since this distribution coefficient suggests a loss from the CNS compartment by a passive transport mechanism to be unlikely.…”

mentioning

confidence: 99%

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From the Ganglioside GQ1b? to Glycomimetic Antagonists of the Myelin-Associated Glycoprotein (MAG)

Ernst

Schwardt²,

Mesch³

et al. 2010

Chimia

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Thetetrasaccharide4,asubstructureofgangliosideGQ1bα,showsaremarkableaffinityforthemyelinassociatedglycoprotein(MAG)andwasthereforeselectedasstartingpointforaleadoptimizationprogram.Inour searchforstructurallysimplifiedandpharmacokineticallyimprovedmimicsof4,antagonistswithmodificationsof thecoredisaccharideGalb(1-3)GalNAc,aswellastheterminalα(2-3)-andtheinternalα(2-6)-linkedneuraminic acidweresynthesizedandtestedintarget-basedbindingassays.Comparedtothereferencetetrasaccharide4, themostpotentantagonist17exhibitsa360-foldimprovedaffinity.Furthermore,pharmacokineticparameters suchasstabilityinthecerebrospinalfluid,logDandpermeationthroughtheBBBindicatethedrug-likepropertiesofantagonist17.

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Section: Design Of Glycomimeticsmentioning

confidence: 64%

“…Combined with the most successful modification of the 9-position of the α(2-3)-linked Neu5Ac (Scheme 2) antagonist 29 with low micromolar affinity could be identified (Scheme 4). [30] …”

Section: Lipophilic and Hydrophilic Replacements Of The α(2-6)-linkedmentioning

confidence: 99%

Section: Determination Of Affinity For Magmentioning

confidence: 99%

Section: Determination Of Affinity For Magmentioning

confidence: 99%

mentioning

confidence: 99%

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From the Ganglioside GQ1b? to Glycomimetic Antagonists of the Myelin-Associated Glycoprotein (MAG)

Ernst

Schwardt²,

Mesch³

et al. 2010

Chimia

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A Fragment‐Based In Situ Combinatorial Approach To Identify High‐Affinity Ligands for Unknown Binding Sites

et al. 2010

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With his publication "On the attribution and additivity of binding energies" in 1981, Jencks [1] launched a new area in medicinal chemistry, that is, the so-called fragment-based drug discovery (FBDD). [2] When fragments are linked, their individual binding energies are additive. In addition, because of the reduction of translational and rigid body rotational degrees of freedom, the entropy barrier is markedly lowered. [3] Thus, by linking two low-affinity fragments, a new ligand with a substantially improved affinity for the target can be generated. However, this intriguing concept resulted in only a few scattered applications [4,5] and had no immediate impact on drug discovery. For a practical application of this strategy two problems remained to be solved; firstly, how suitable fragments that bind to proximal binding sites (socalled first-and second-site fragments) can be identified, and secondly, how these fragments can be linked without distortions of their individual binding modes.The rapid development of this promising area [6] was initiated in 1996, when a conclusive practical demonstration of FBDD, called structure-affinity relationship by NMR (SAR-by-NMR) was reported. [7] With this novel approach, antagonists with nanomolar affinities were rapidly identified by tethering two fragments that were individually optimized by NMR spectroscopy. However, the implementation range of this technique was limited by the requirement for labeled proteins ( 13 C and 15 N) and for structural information on the binding site in order to design the linker. Subsequently, a broad array of innovative strategies for screening fragments were reported, for example, the needle approach [5] or tethering techniques detected by mass spectrometry. [8] Furthermore, the problem of the linker design was addressed by, for example, Sharpless and co-workers, [9] who used the target itself as an atomic-scale reaction vessel for creating its own inhibitor or by applying a shape-modulating linker design. [10] Herein we present a novel fragment-based approach that does not require any spatial information on the binding site and can be conducted with modest amounts of unlabeled protein. Our target is the myelin-associated glycoprotein (MAG, Siglec-4), a sialic acid binding immunoglobulin-like lectin (Siglec), [11] which inhibits as one of several myelin components axonal regrowth after injury. [12] The recently reported use of monovalent glycosides [13] to reverse MAGmediated blocking of axonal regeneration encouraged the search for high-affinity ligands. Oligo-and monosaccharide derivatives based on the ganglioside GQ1ba, [14] which was the hitherto best reported natural MAG antagonist, exhibit only micromolar affinities. [15] Therefore, an alternative approach to identify high-affinity ligands was required.Because the crystal structure of MAG is not yet available, a homology model [16] based on the crystal structure of sialoadhesin (Siglec-1), [17] another member of the Siglec family, was investigated. This model revealed a shallow, unstruc...

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A Fragment‐Based In Situ Combinatorial Approach To Identify High‐Affinity Ligands for Unknown Binding Sites

et al. 2010

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View full text Add to dashboard Cite

With his publication "On the attribution and additivity of binding energies" in 1981, Jencks [1] launched a new area in medicinal chemistry, that is, the so-called fragment-based drug discovery (FBDD).[2] When fragments are linked, their individual binding energies are additive. In addition, because of the reduction of translational and rigid body rotational degrees of freedom, the entropy barrier is markedly lowered.[3] Thus, by linking two low-affinity fragments, a new ligand with a substantially improved affinity for the target can be generated. However, this intriguing concept resulted in only a few scattered applications [4,5] and had no immediate impact on drug discovery. For a practical application of this strategy two problems remained to be solved; firstly, how suitable fragments that bind to proximal binding sites (socalled first-and second-site fragments) can be identified, and secondly, how these fragments can be linked without distortions of their individual binding modes.The rapid development of this promising area [6] was initiated in 1996, when a conclusive practical demonstration of FBDD, called structure-affinity relationship by NMR (SAR-by-NMR) was reported. [7] With this novel approach, antagonists with nanomolar affinities were rapidly identified by tethering two fragments that were individually optimized by NMR spectroscopy. However, the implementation range of this technique was limited by the requirement for labeled proteins ( 13 C and 15 N) and for structural information on the binding site in order to design the linker. Subsequently, a broad array of innovative strategies for screening fragments were reported, for example, the needle approach [5] or tethering techniques detected by mass spectrometry.[8] Furthermore, the problem of the linker design was addressed by, for example, Sharpless and co-workers, [9] who used the target itself as an atomic-scale reaction vessel for creating its own inhibitor or by applying a shape-modulating linker design.[10]Herein we present a novel fragment-based approach that does not require any spatial information on the binding site and can be conducted with modest amounts of unlabeled protein. Our target is the myelin-associated glycoprotein (MAG, Siglec-4), a sialic acid binding immunoglobulin-like lectin (Siglec), [11] which inhibits as one of several myelin components axonal regrowth after injury.[12] The recently reported use of monovalent glycosides [13] to reverse MAGmediated blocking of axonal regeneration encouraged the search for high-affinity ligands. Oligo-and monosaccharide derivatives based on the ganglioside GQ1ba, [14] which was the hitherto best reported natural MAG antagonist, exhibit only micromolar affinities.[15] Therefore, an alternative approach to identify high-affinity ligands was required.Because the crystal structure of MAG is not yet available, a homology model [16] based on the crystal structure of sialoadhesin (Siglec-1), [17] another member of the Siglec family, was investigated. This model revealed a shallow, unstructured b...

show abstract

Examination of the Biological Role of the α(2→6)-Linked Sialic Acid in Gangliosides Binding to the Myelin-Associated Glycoprotein (MAG)

Cited by 23 publications

References 78 publications

From the Ganglioside GQ1b? to Glycomimetic Antagonists of the Myelin-Associated Glycoprotein (MAG)

From the Ganglioside GQ1b? to Glycomimetic Antagonists of the Myelin-Associated Glycoprotein (MAG)

A Fragment‐Based In Situ Combinatorial Approach To Identify High‐Affinity Ligands for Unknown Binding Sites

A Fragment‐Based In Situ Combinatorial Approach To Identify High‐Affinity Ligands for Unknown Binding Sites

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