Cyclodextrin-Adamantane Host–Guest Interactions on the Surface of Biocompatible Adamantyl-Modified Glycodendrimers

A series of adamantyl-modified glycodendrimers (<b>mPPI-Gx-AdaA-C</b>) was prepared in a two-step synthesis using two efficient reactions: (1) urea bond formation from amine and isocyanate and (2) reductive amination. ¹H NMR spectroscopy (host guest titration and ROESY experiments) was used to evaluate the graded effect of steric hindrance as a function of the number and type of oligosaccharide molecules and of the number of adamantyl (Ada) units on the complexation with monomeric β-cyclodextrin (β-CD). Glycosylated fourth generation PPIs showing an average substitution in adamantyl groups of 13% were found to interact with β-CD effectively, and were considered as candidates for further complexation studies with a polymeric cyclodextrin derivative (<i>poly-</i>β-CD). The host–guest interaction features of the maltosylated dense shell glycodendrimer along with the low cytotoxicity provided the rational basis for the use of these adamantyl-functionalized glycodendrimers in the design of supramolecular systems potentially useful as healthcare materials

Laser-Induced Liquid Bead Ion Desorption Mass Spectrometry: An Approach to Precisely Monitor the Oligomerization of the β-Amyloid Peptide

In the present work, the recently developed laser-induced liquid bead ion desorption mass spectrometry (LILBID MS) is applied as a novel technique to study Aβ oligomerization, thought to be crucial in Alzheimer’s disease (AD). The characterization of the earliest nucleation events of this peptide necessitates the application of several techniques to bridge the gap between small oligomers and large fibrils. We precisely monitored in time the transformation of monomeric Aβ (1-42) into oligomeric Aβ_<i>n</i> (<i>n</i> < 20) and its dependence on concentration and agitation. The distribution shows signs of the hexamer being crucial in the assembly process. The intensity of the monomer decreases in time with a time constant of about 9 h. After a lag time of around 10 h, a phase transition occurred in which the total ion current of the oligomers goes to nearly zero. In this late stage of aggregation, protofibrils are formed and mass spectrometry is no longer sensitive. Here fluorescence correlation spectroscopy (FCS) and transmission electron microscopy (TEM) are complementary tools for detection and size characterization of these large species. We also utilized the oligomers of Aβ (1-42) as a model of the corresponding <i>in vivo</i> process to screen the efficacy and specificity of small molecule inhibitors of oligomerization. The LILBID results are in excellent agreement with condensed phase behavior determined in other studies. Our data identified LILBID MS as a powerful technique that will advance the understanding of peptide oligomerization in neurodegenerative diseases and represents a powerful tool for the identification of small oligomerization inhibitors