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  • Structural characterisation of high affinity Siglec-2 (CD22) ligands in complex with whole Burkitt's lymphoma (BL) Daudi cells by NMR spectroscopy

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    Author(s)
    Madge, Paul D
    Maggioni, Andrea
    Pascolutti, Mauro
    Amin, Moein
    Waespy, Mario
    Bellette, Bernadette
    Thomson, Robin J
    Kelm, Sorge
    von Itzstein, Mark
    Haselhorst, Thomas
    Griffith University Author(s)
    von Itzstein, Mark
    Thomson, Robin J.
    Haselhorst, Thomas E.
    Madge, Paul D.
    Maggioni, Andrea
    Bellette, Bernadette
    Kelm, Soerge
    Pascolutti, Mauro
    Amin, Moein
    Year published
    2016
    Metadata
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    Abstract
    Siglec-2 undergoes constitutive endocytosis and is a drug target for autoimmune diseases and B cellderived malignancies, including hairy cell leukaemia, marginal zone lymphoma, chronic lymphocytic leukaemia and non-Hodgkin’s lymphoma (NHL). An alternative to current antibody-based therapies is the use of liposomal nanoparticles loaded with cytotoxic drugs and decorated with Siglec-2 ligands. We have recently designed the first Siglec-2 ligands (9-biphenylcarboxamido-4-meta-nitrophenylcarboxamido- Neu5Acα2Me, 9-BPC-4-mNPC-Neu5Acα2Me) with simultaneous modifications at C-4 and C-9 position. In the current study we have used ...
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    Siglec-2 undergoes constitutive endocytosis and is a drug target for autoimmune diseases and B cellderived malignancies, including hairy cell leukaemia, marginal zone lymphoma, chronic lymphocytic leukaemia and non-Hodgkin’s lymphoma (NHL). An alternative to current antibody-based therapies is the use of liposomal nanoparticles loaded with cytotoxic drugs and decorated with Siglec-2 ligands. We have recently designed the first Siglec-2 ligands (9-biphenylcarboxamido-4-meta-nitrophenylcarboxamido- Neu5Acα2Me, 9-BPC-4-mNPC-Neu5Acα2Me) with simultaneous modifications at C-4 and C-9 position. In the current study we have used Saturation Transfer Difference (STD) NMR spectroscopy to monitor the binding of 9-BPC-4-mNPC-Neu5Acα2Me to Siglec-2 present on intact Burkitt’s lymphoma Daudi cells. Pre-treatment of cells with periodate resulted in significantly higher STD NMR signal intensities for 9-BPC-4-mNPC-Neu5Acα2Me as the cells were more susceptible to ligand binding because cis-binding on the cell surface was removed. Quantification of STD NMR effects led to a cell-derived binding epitope of 9-BPC-4-mNPC-Neu5Acα2Me that facilitated the design and synthesis of C-2, C-3, C-4 and C-9 tetra-substituted Siglec-2 ligands showing an 88-fold higher affinity compared to 9-BPC-Neu5Acα2Me. This is the first time a NMR-based binding study of high affinity Siglec-2 (CD22) ligands in complex with whole Burkitt’s lymphoma Daudi cells has been described that might open new avenues in developing tailored therapeutics and personalised medicine.
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    Journal Title
    Scientific Reports
    Volume
    6
    DOI
    https://doi.org/10.1038/srep36012
    Copyright Statement
    © The Author(s). 2016. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
    Subject
    Biochemistry and Cell Biology not elsewhere classified
    Publication URI
    http://hdl.handle.net/10072/100671
    Collection
    • Journal articles

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