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  • Discovery of novel glycomimetic ligands for Siglec-8 = Odkrivanje novih glikomimetičnih ligandov za Siglec-8 : doktorska disertacija
    Girardi, Benedetta
    This thesis principally focuses on the development of glycomimetic ligands with improved affinity to Siglec-8. Siglec-8 is a member of the Siglec family, I-type lectins that contain a sialic ... acid-binding domain and that play different roles in cell-cell interactions and cell signaling. Siglec-8 is a CD33- related protein expressed exclusively on mast cells and eosinophils, and weakly on basophils. Crosslinking of Siglec-8 with antibodies leads to apoptosis of eosinophils and inhibition of degranulation of mast cells. Apoptosis has also been induced when eosinophils were treated with a glycopolymer (6’-sulfo-sLex-polyacrylamide polymer). Therefore, Siglec-8 represents a very interesting new pharmacological target for the treatment of eosinophil- or mast cell-associated diseases, such as asthma, chronic rhinosinusitis, chronic urticaria, hypereosinophilic syndromes, mast cell and eosinophil malignancies, and eosinophilic gastrointestinal disorders. Recently, the NMR solution structure of the Siglec-8 lectin domain was solved in complex with its preferred ligand, the tetrasaccharide 6′-sulfo sialyl Lewisx (Neu5Acα2-3[6S]Galβ1-4[Fucα1-3]GlcNAc). The main interactions involve a salt bridge between Arg109 and the carboxylate of sialic acid and a second salt bridge between Arg56 and Gln59 and the sulfate at the 6-position of the galactose moiety. Interestingly, the sulfate plays a key role in both binding and specificity to Siglec-8. In addition, hydrogen bonds exist between hydroxyl groups 7, 8 and 9 of sialic acid and Tyr7, Ser118 and Gln122. In contrast, the fucose and glucosamine subunits show only minor interactions. This led to the suggestion that the disaccharide substructure 6-sulfo-Sia-Gal might represent the minimal binding epitope for Siglec-8.
    Vrsta gradiva - disertacija ; neleposlovje za odrasle
    Založništvo in izdelava - Ljubljana : [B. M. Girardi], 2023
    Jezik - slovenski
    COBISS.SI-ID - 143703811

Knjižnica/institucija Kraj Akronim Za izposojo Druga zaloga
Centralna tehniška knjižnica Univerze v Ljubljani Ljubljana CTK na dom 1 izv.
Fakulteta za farmacijo, Ljubljana Ljubljana FFALJ v čitalnico 1 izv.
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