Discovery of novel glycomimetic ligands for Siglec-8 : doctoral dissertation

english

doktorska dela

2022

Univerza v Ljubljani, Fakulteta za farmacijo
(Obvezni izvod spletne publikacije)

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 (Neu5Ac?2-36SGalß1-4Fuc?1-3GlcNAc). 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.

12.05.2023