Structure-Guided Design of Sialic Acid-Based Siglec Inhibitors and Crystallographic Analysis in Complex with Sialoadhesin

Zaccai, Nathan R.; Maenaka, Katsumi; Maenaka, T; Crocker, Paul R.; Brossmer, Reinhard; Kelm, Sørge; Jones, E Y

doi:10.1016/s0969-2126(03)00073-x

Cited by 101 publications

(135 citation statements)

References 51 publications

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“…This key difference must be taken into account in the rational design of inhibitors for each ortholog of CD22. Modeling studies of Zaccai et al (50) indicated a hydrophobic pocket in CD22 adjacent to the 9-position of sialic acid, and further identified biphenyl substituents at that position, BPC and BPA, that increased the affinity of NeuAc for hCD22 and mCD22, respectively (50,56). Using a chemoenzymatic approach (33, 41), we assembled the specificity elements preferred by hCD22 and mCD22 into the sequences 9-BPC-NeuAc␣2-6Gal␤1-4GlcNAc␤-ethylamine (BPC-NeuAc-LN) and 9-BPA-NeuGc␣2-6Gal␤1-4GlcNAc␤-ethylamine (BPA-NeuGc-LN), resulting in inhibitory potencies (IC 50 values) of 1-2 M for hCD22 and mCD22, respectively ( Fig.…”

Section: Development Of High-affinity Sialoside Ligands Of Cd22mentioning

confidence: 99%

“…To create high-affinity probes for B cell targeting, we combined molecular features previously reported to enhance the affinity for CD22. Accordingly, 9-biphenyl substituents of sialic acid shown by Zaccai et al (50) to increase the affinity of CD22 were incorporated into the preferred sialoside ligands of human and murine CD22, and subsequently attached to a high m.w. polyacrylamide backbone to provide a highly multivalent construct.…”

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confidence: 99%

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High-Affinity Ligand Probes of CD22 Overcome the Threshold Set by cis Ligands to Allow for Binding, Endocytosis, and Killing of B Cells

Collins

Blixt

Han

et al. 2006

The Journal of Immunology

146

212

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CD22 (Siglec-2) is a key regulator of B cell signaling whose function is modulated by interaction with extracellular glycan ligands mediated through its N-terminal Ig domain. Its preferred ligand is the sequence Siaα2-6Gal that is abundantly expressed on N-linked glycans of B cell glycoproteins, and by binding to CD22 in cis causes CD22 to appear “masked” from binding to synthetic sialoside probes. Yet, despite the presence of cis ligands, CD22 redistributes to sites of cell contact by binding to trans ligands on neighboring cells. In this study, we demonstrate the dynamic equilibrium that exists between CD22 and its cis and trans ligands, using a high-affinity multivalent sialoside probe that competes with cis ligands and binds to CD22 on native human and murine B cells. Consistent with the constitutive endocytosis reported for CD22, the probes are internalized once bound, demonstrating that CD22 is an endocytic receptor that can carry ligand-decorated “cargo” to intracellular compartments. Conjugation of the sialoside probes to the toxin saporin resulted in toxin uptake and toxin-mediated killing of B lymphoma cell lines, suggesting an alternative approach for targeting CD22 for treatment of B cell lymphomas.

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Section: Development Of High-affinity Sialoside Ligands Of Cd22mentioning

confidence: 99%

mentioning

confidence: 99%

High-Affinity Ligand Probes of CD22 Overcome the Threshold Set by cis Ligands to Allow for Binding, Endocytosis, and Killing of B Cells

Collins

Blixt

Han

et al. 2006

The Journal of Immunology

146

212

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“…Sialic acids are afamily comprising of over 40 kinds of derivatives of N-acetylneuraminicacid(Neu5Ac), with structural diversity generatedbys ubstitutions at thecarbonpositions 4, 5, 7, 8 and9 [1,2],which can take part in alarge variety of biological functions including recognition phenomena [3].Asconsequence, they are usually exploited as anti-influenza drugs and substrates of detecting influenza [4,5].Inthis work, we present aderivative, namely 4,7-di-O-methyl 8,9-O-isopropylidine Neu5Ac methyl estermethylketoside. Crystalstructure and spectroscopic characterization ared escribed herein.T he unit cell of this compound contains four 4,7-di-O-methyl 8,9-O-isopropylidine Neu5Ac methyl ester methyl ketoside molecules.…”

Section: Discussionmentioning

confidence: 99%

“…All Hatoms on Catoms were generated geometrically andrefined as riding atomsw ith d(C-H) =0 .96-0.98 Å, and U iso (H) =1 .2 U eq (C) for Ca toms of CH 2 and CH groups and U iso (H) =1 .5 U eq (C) for Catoms of CH 3 groups. The hydrogen atom of the N1 atom has been added on the basis of the Q peak, the bond H-N has been constrained with 'dfix' command in ad istance of 0.82 Å, with adeviation of 0.01.…”

Section: Methodsmentioning

confidence: 99%

Crystal structure of 4,7-di-O-methyl 8,9-O-isopropylidine Neu5Ac methyl ester methyl ketoside, C18H31NO9

Zhou

al.²

2012

Zeitschrift für Kristallographie - New Crystal Structures

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“…Regardless, a 10 M concentration of disialyl T antigen was efficacious, and the toxicity of saccharides is characteristically low. Thus, testing of sialoglycans for their ability to enhance axon regeneration in nerve injury models in vivo may be feasible and provides impetus for identifying further structural refinements that may generate yet higher affinity sialoglycan inhibitors (51).…”

Section: Fig 6 Benzyl-␣-galnac Treatment Does Not Reverse Mag-mediamentioning

confidence: 99%

Potent Glycan Inhibitors of Myelin-associated Glycoprotein Enhance Axon Outgrowth in Vitro

Vyas¹,

Blixt

Paulson

et al. 2005

Journal of Biological Chemistry

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Myelin-associated glycoprotein (MAG, Siglec-4) is one of several endogenous axon regeneration inhibitors that limit recovery from central nervous system injury and disease. Molecules that block such inhibitors may enhance axon regeneration and functional recovery. MAG, a member of the Siglec family of sialic acid-binding lectins, binds to sialoglycoconjugates on axons and particularly to gangliosides GD1a and GT1b, which may mediate some of the inhibitory effects of MAG. In a prior study ( The injured adult mammalian central nervous system (CNS) 1 is a highly inhibitory environment for axon regeneration, in large part due to specific axon regeneration inhibitors expressed on residual myelin that persists at sites of CNS injury and on astrocytes recruited to injury sites (1-3). The inhibitors include three myelin proteins, myelin-associated glycoprotein (MAG), Nogo, and oligodendrocyte-myelin glycoprotein (OMgp), and chondroitin sulfate proteoglycans, which are found on the astrocytic scar and on residual myelin. Axon regeneration inhibitors, on myelin and astrocytes, bind specifically to targets on the axon surface, initiating a signaling cascade that ultimately activates RhoA and halts axon outgrowth by modulating actin dynamics. Detailed knowledge of axon regeneration inhibitors, their axonal ligands, and the signaling pathways leading to changes in the actin cytoskeleton promises to provide opportunities to enhance axon regeneration after CNS injury (e.g. spinal cord injury) and in diseases involving axon loss, such as multiple sclerosis, Parkinson disease, and Alzheimer disease.MAG has two classes of well-defined axonal targets: sialylated glycans, specifically gangliosides GD1a and GT1b (4), and the glycosylphosphatidylinositol-linked proteins of the NgR family, NgR1 (5, 6) and NgR2 (7), which may also be axonal ligands for Nogo and OMgp (8). There are conflicting data concerning the sialidase sensitivity of MAG-NgR binding (5-7).Although the relative roles of gangliosides and NgRs as MAG ligands have yet to be resolved, in some systems MAG inhibition is completely reversed by sialidase, suggesting that, at least in those systems, MAG uses sialylated glycans as its major axonal ligands. In those systems, or in combination with blockers of NgR (9), it is anticipated that potent glycan inhibitors of MAG may be valuable tools to enhance axon regeneration.MAG (Siglec-4), a member of the Siglec (sialic acid-binding immunoglobulin-like lectin) family (10), binds preferentially to the terminal sequence "NeuAc␣2-3Gal␤1-3GalNAc" (11), especially in the context of larger glycan structures bearing additional anionic groups (see Fig. 1). In the brain, this structure is most abundant as the terminus of gangliosides GD1a and GT1b, which are high-affinity MAG ligands and mediate MAG inhibition of axon outgrowth in vitro (4, 12). Glycan structures with an additional sialic acid 6-linked to the GalNAc residue, "NeuAc␣2-3Gal␤1-3(NeuAc␣2-6)GalNAc," bind to MAG with an order of magnitude higher affinity than the correspondin...

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Structure-Guided Design of Sialic Acid-Based Siglec Inhibitors and Crystallographic Analysis in Complex with Sialoadhesin

Cited by 101 publications

References 51 publications

High-Affinity Ligand Probes of CD22 Overcome the Threshold Set by cis Ligands to Allow for Binding, Endocytosis, and Killing of B Cells

High-Affinity Ligand Probes of CD22 Overcome the Threshold Set by cis Ligands to Allow for Binding, Endocytosis, and Killing of B Cells

Crystal structure of 4,7-di-O-methyl 8,9-O-isopropylidine Neu5Ac methyl ester methyl ketoside, C18H31NO9

Potent Glycan Inhibitors of Myelin-associated Glycoprotein Enhance Axon Outgrowth in Vitro

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