GalNAc mimetics: from synthesis to potential inhibitors in Alzheimer’s Disease

N-acetylgalactosamine(GalNAc) belongs to the group of 2-amino-2-deoxysugars which are found in a wide range of biological structures playing a role in in cell-cell interaction and receptor induced cell signaling, among other biological processes in health and disease.

Alzheimer’s disease (AD) is a protein misfolding pathology, causing dementia in over 40 million people worldwide. Cellular prion protein (PrP) has a high-affinity binding with amyloid β (Aβ) oligomers, the most toxic species in Alzheimer’s pathology¹. It has been demonstrated that O-glycosylated GalNAc, attached to Ser/Thr side chain of PrP via an α-glycosidic linkage, promotes the inhibition of amyloidogenesis in AD². In this context, we have synthesized new GalNAc mimetics, including phenyl selenogalactosides with additional contacts in the GalNAc core structure, to improve the interactions with the prion peptide and to investigate the binding affinity with Aβ_1-42. The study of the intermolecular interactions of the new chemical structures and Aβ_1-42 oligomers was investigated by NMR methods, namely saturation transfer difference NMR (STD-NMR) and ¹⁹Fluorine NMR (F-NMR) protocols. Different methods, such as rapid equilibrium diffusion (RED) were applied for the evaluation of interactions. At the same time, competition and metabolic experiments were carried out. In this communication, synthetic approaches to the GalNAc mimetics will be presented and interaction results regarding C2 substitution and anomeric heteroatoms, such as O, S and Se with Aβ_1-42 oligomers will be discussed.

References:

1. Blázquez-Sánchez, M.T., Matos, A.M., Rauter, A.P., Exploring Anti-Prion Glyco-Based and Aromatic Scaffolds: A Chemical Strategy for the Quality of Life, Molecules, (2017), 22-26;

2. Lin, C., Chen, E., Lee, L., Hsu, R., Luh, F., Yand, L., Chou, C., Huang, L., Lin, C., Chen, R., Comparison of the anti-amyloidogenic effect of O-mannosylation, O-galactosylation and O-GalNAc glycosylation, Carbohydr. Res.,(2014), 46-53.