Synthesis and Molecular Recognition Studies of the HNK-1 Trisaccharide and Related Oligosaccharides. The Specificity of Monoclonal Anti-HNK-1 Antibodies as Assessed by Surface Plasmon Resonance and STD NMR

Tsvetkov, Yury E.; Burg‐Roderfeld, Monika; Loers, Gabriele; Ardá, Ana; Сухова, Е. В.; Khatuntseva, Elena A.; Грачев, А. А.; Chizhov, Alexander O.; Siebert, Hans‐Christian; Schachner, Melitta; Jiménez‐Barbero, Jesús; Nifantiev, Nikolay E.

doi:10.1021/ja2083015

Cited by 86 publications

(58 citation statements)

References 54 publications

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“…[70] The molecular recognition of HNK-1 trisaccharide and related oligosaccharides by Anti-HNK-1 antibodies, has been recently investigated by using SPR and STD-NMR experiments. [71] In order to assess the specificity of monoclonal HNK-1 antibodies, different HNK-1 carbohydrates were synthesized. SPR revealed the significance of the glucuronic acid in antibody recognition, while STD-NMR allowed disclosing the contribution of the different oligosaccharide moieties in the interaction HNK-1 pentasaccharide and the HNK-1 412 antibody.…”

Section: Protein-carbohydrate Interactions In Health and Diseasementioning

confidence: 99%

Protein-Carbohydrate Interactions Studied by NMR: From Molecular Recognition to Drug Design

Fernández‐Alonso¹,

Díaz²,

Berbís³

et al. 2012

CPPS

121

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Diseases that result from infection are, in general, a consequence of specific interactions between a pathogenic organism and the cells. The study of host-pathogen interactions has provided insights for the design of drugs with therapeutic properties. One area that has proved to be promising for such studies is the constituted by carbohydrates which participate in biological processes of paramount importance. On the one hand, carbohydrates have shown to be information carriers with similar, if not higher, importance than traditionally considered carriers as amino acids and nucleic acids. On the other hand, the knowledge on molecular recognition of sugars by lectins and other carbohydrate-binding proteins has been employed for the development of new biomedical strategies. Biophysical techniques such as X-Ray crystallography and NMR spectroscopy lead currently the investigation on this field. In this review, a description of traditional and novel NMR methodologies employed in the study of sugar-protein interactions is briefly presented in combination with a palette of NMR-based studies related to biologically and/or pharmaceutically relevant applications.

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Section: Protein-carbohydrate Interactions In Health and Diseasementioning

confidence: 99%

Protein-Carbohydrate Interactions Studied by NMR: From Molecular Recognition to Drug Design

Fernández‐Alonso¹,

Díaz²,

Berbís³

et al. 2012

CPPS

121

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“…After MAG deglycosylation, the patients' autoantibodies lose their MAG reactivity (42). Saturation transfer difference (STD) NMR experiments revealed that the terminal trisaccharide SO 3 -3-GlcA(β1-3)Gal(β1-4)GlcNAc, i.e., the HNK-1 epitope, of the glycolipid SGPG interacts with the mouse monoclonal anti-HNK-1 IgM and that the most significant contribution is made by the terminal disaccharide SO 3 -3-GlcA(β1-3)Gal (43). In this study, we synthesized a glycomimetic of the natural HNK-1 trisaccharide epitope.…”

Section: Discussionmentioning

confidence: 99%

Selective in vivo removal of pathogenic anti-MAG autoantibodies, an antigen-specific treatment option for anti-MAG neuropathy

Herrendorff

Hänggi

Pfister

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Anti-MAG (myelin-associated glycoprotein) neuropathy is a disabling autoimmune peripheral neuropathy caused by monoclonal IgM autoantibodies that recognize the carbohydrate epitope HNK-1 (human natural killer-1). This glycoepitope is highly expressed on adhesion molecules, such as MAG, present in myelinated nerve fibers. Because the pathogenicity and demyelinating properties of anti-MAG autoantibodies are well established, current treatments are aimed at reducing autoantibody levels. However, current therapies are primarily immunosuppressive and lack selectivity and efficacy. We therefore hypothesized that a significant improvement in the disease condition could be achieved by selectively neutralizing the pathogenic anti-MAG antibodies with carbohydrate-based ligands mimicking the natural HNK-1 glycoepitope 1. In an inhibition assay, a mimetic (2, mimHNK-1) of the natural HNK-1 epitope blocked the interaction of MAG with pathogenic IgM antibodies from patient sera but with only micromolar affinity. Therefore, considering the multivalent nature of the MAG-IgM interaction, polylysine polymers of different sizes were substituted with mimetic 2. With the most promising polylysine glycopolymer PL 84 (mimHNK-1) 45 the inhibitory effect on patient sera could be improved by a factor of up to 230,000 per epitope, consequently leading to a lownanomolar inhibitory potency. Because clinical studies indicate a correlation between the reduction of anti-MAG IgM levels and clinical improvement, an immunological surrogate mouse model for anti-MAG neuropathy producing high levels of anti-MAG IgM was developed. The observed efficient removal of these antibodies with the glycopolymer PL 84 (mimHNK-1) 45 represents an important step toward an antigen-specific therapy for anti-MAG neuropathy.demyelinating peripheral neuropathy | IgM autoantibodies | myelinassociated glycoprotein | HNK-1 glycoepitope | glycosylated polylysine

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“…Glycofulleren molecules inhibit the infection by pseudo-typed Ebola virus particles [54]. Tsvetkov et al [55] employed STD-NMR methods to explore the binding epitope of HNK-1 (human natural killer cell carbohydrate) pentasaccharide to HNK-1 412 antibody. Due to heavy overlapping in STD experiment, STD-TOCSY experiment was performed to resolve the STD signals in a second dimension.…”

Section: Sugar-protein Interactionmentioning

confidence: 99%

Recent Advances in NMR Studies of Carbohydrates

Buda¹,

Nawój²,

Młynarski³

2016

Annual Reports on NMR Spectroscopy

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Synthesis and Molecular Recognition Studies of the HNK-1 Trisaccharide and Related Oligosaccharides. The Specificity of Monoclonal Anti-HNK-1 Antibodies as Assessed by Surface Plasmon Resonance and STD NMR

Cited by 86 publications

References 54 publications

Protein-Carbohydrate Interactions Studied by NMR: From Molecular Recognition to Drug Design

Protein-Carbohydrate Interactions Studied by NMR: From Molecular Recognition to Drug Design

Selective in vivo removal of pathogenic anti-MAG autoantibodies, an antigen-specific treatment option for anti-MAG neuropathy

Recent Advances in NMR Studies of Carbohydrates

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