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Conformationally Constrained Sialyl Analogues as New Potential Binders of h‐CD22

Here, two conformationally constrained sialyl analogues were synthesized and characterized in their interaction with the inhibitory Siglec, human CD22 (h‐CD22). An orthogonal approach, including biophysical assays (SPR and fluorescence), ligand‐based NMR techniques, and molecular modelling, was empl...

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Detalles Bibliográficos
Autores principales: Forgione, Rosa Ester, Nieto, Ferran Fabregat, Di Carluccio, Cristina, Milanesi, Francesco, Fruscella, Martina, Papi, Francesco, Nativi, Cristina, Molinaro, Antonio, Palladino, Pasquale, Scarano, Simona, Minunni, Maria, Montefiori, Marco, Civera, Monica, Sattin, Sara, Francesconi, Oscar, Marchetti, Roberta, Silipo, Alba
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9315041/
https://www.ncbi.nlm.nih.gov/pubmed/35313057
http://dx.doi.org/10.1002/cbic.202200076
Descripción
Sumario:Here, two conformationally constrained sialyl analogues were synthesized and characterized in their interaction with the inhibitory Siglec, human CD22 (h‐CD22). An orthogonal approach, including biophysical assays (SPR and fluorescence), ligand‐based NMR techniques, and molecular modelling, was employed to disentangle the interaction mechanisms at a molecular level. The results showed that the Sialyl‐TnThr antigen analogue represents a promising scaffold for the design of novel h‐CD22 inhibitors. Our findings also suggest that the introduction of a biphenyl moiety at position 9 of the sialic acid hampers canonical accommodation of the ligand in the protein binding pocket, even though the affinity with respect to the natural ligand is increased. Our results address the search for novel modifications of the Neu5Ac‐α(2‐6)‐Gal epitope, outline new insights for the design and synthesis of high‐affinity h‐CD22 ligands, and offer novel prospects for therapeutic intervention to prevent autoimmune diseases and B‐cell malignancies.