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

Abstract

: 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. 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 pathology. 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 AD. In this context, we have synthesized new GalNAc mimetics, 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 19 Fluorine NMR (F-NMR) protocols. 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. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature 2009; 457:1128-32.