ArticleBioorganic & medicinal chemistry letters2011
High affinity sialoside ligands of myelin associated glycoprotein.
Article in Bioorganic & medicinal chemistry letters, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 20 citations in OpenAlex.
- Tumor glyco-immunology, glyco-immune checkpoints and immunotherapy.Journal for immunotherapy of cancer · 2025Review
- Enzyme-Sialylation-Controlled Chemical Sulfation of Glycan Epitopes for Decoding the Binding of Siglec Ligands.Journal of the American Chemical Society · 2024Article
- Glycomimetics for the inhibition and modulation of lectins.Chemical Society reviews · 2023Review
- Promotion effect of the blend containing 2'-FL, OPN and DHA on oligodendrocyte progenitor cells myelinationFrontiers in nutrition · 2022Article
- Siglec Ligands.Cells · 2021Review
- Probing the binding specificities of human Siglecs by cell-based glycan arrays.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Why Is Eradicating Typhoid Fever So Challenging: Implications for Vaccine and Therapeutic Design.Vaccines · 2018Review
- CD22-Binding Synthetic Sialosides Regulate B Lymphocyte Proliferation Through CD22 Ligand-Dependent and Independent Pathways, and Enhance Antibody Production in Mice.Frontiers in immunology · 2018Article
- Therapeutic Targeting of Siglecs using Antibody- and Glycan-Based Approaches.Trends in pharmacological sciences · 2015Review
- Design and syntheses of hyaluronan oligosaccharide conjugates as inhibitors of CD44-Hyaluronan binding.Glycoconjugate journal · 2015Article
- Disubstituted Sialic Acid Ligands Targeting Siglecs CD33 and CD22 Associated with Myeloid Leukaemias and B Cell Lymphomas.Chemical science · 2014Article
- On-chip synthesis and screening of a sialoside library yields a high affinity ligand for Siglec-7.ACS chemical biology · 2013Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Myelin associated glycoprotein (Siglec-4) is a myelin adhesion receptor, that is, well established for its role as an inhibitor of axonal outgrowth in nerve injury, mediated by binding to sialic acid containing ligands on the axonal membrane. Because disruption of myelin-ligand interactions promotes axon outgrowth, we have sought to develop potent ligand based inhibitors using natural ligands as scaffolds. Although natural ligands of MAG are glycolipids terminating in the sequence NeuAcα2-3Galβ1-3(±NeuAcα2-6)GalNAcβ-R, we previously established that synthetic O-linked glycoprotein glycans with the same sequence α-linked to Thr exhibited ∼1000-fold increased affinity (∼1μM). Attempts to increase potency by introducing a benzoylamide substituent at C-9 of the α2-3 sialic acid afforded only a two-fold increase, instead of increases of >100-fold observed for other sialoside ligands of MAG. Surprisingly, however, introduction of a 9-N-fluoro-benzoyl substituent on the α2-6 sialic acid increased affinity 80-fold, resulting in a potent inhibitor with a K(d) of 15nM. Docking this ligand to a model of MAG based on known crystal structures of other siglecs suggests that the Thr positions the glycan such that aryl substitution of the α2-3 sialic acid produces a steric clash with the GalNAc, while attaching an aryl substituent to the other sialic acid positions the substituent near a hydrophobic pocket that accounts to the increase in affinity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.