The key pathogenic event in the onset of Alzheimer's disease (AD) is the aggregation of β‐amyloid (Aβ) peptides into toxic aggregates. Molecules that interfere with this process might act as therapeutic agents for the treatment of AD. The amino acid residues 16–20 (KLVFF) are known to be essential for the aggregation of Aβ. In this study, we have used a first‐generation dendrimer as a scaffold for the multivalent display of the KLVFF peptide. The effect of four KLVFF peptides attached to the dendrimer (K4) on Aβ aggregation was compared to the effect of monomeric KLVFF (K1). Our data show that K4 very effectively inhibits the aggregation of low‐molecular‐weight and protofibrillar Aβ1–42 into fibrils, in a concentration‐dependent manner, and much more potently than K1. Moreover, we show that K4 can lead to the disassembly of existing aggregates. Our data lead us to propose that conjugates that bear multiple copies of KLVFF might be useful as therapeutic agents for the treatment of Alzheimer's disease.

A wide variety of well‐defined multivalent peptides and proteins can be made by conjugating synthetic peptides and recombinantly expressed proteins to cysteine‐functionalized dendrimers using native chemical ligation (see picture). This modular approach provides access to dendrimers that are attractive both for understanding fundamental issues of multivalency in biological interactions as well as for biomedical applications.

In the presence of a catalytic amount of copper salts, cinnamyl halides undergo a regio-and enantioselective S N 2′ alkylation with dialkylzincs using chiral phosphoramidites as ligands. An S N 2′:S N 2 ratio of 85:15 and enantiomeric excesses up to 77% for the chiral S N 2′ products are found. Variation of solvent and reaction temperature revealed that the highest regio-and enantioselectivities are found using coordinating solvents of −40 °C.

Eine Vielzahl gut definierter multivalenter Peptide und Proteine ist erhältlich, indem synthetische Peptide und rekombinant exprimierte Proteine mithilfe der nativen chemischen Ligation an Cystein‐funktionalisierte Dendrimere konjugiert werden (siehe Bild). Auf diesem Weg sind Dendrimere zugänglich, die für das Verständnis zentraler Aspekte der Multivalenz in biologischen Wechselwirkungen wie auch für biomedizinische Anwendungen interessant sind.

Water‐soluble guest–host complexes are prepared in a two‐step process. For this a new, polydisperse ethylene glycol containing guest molecule is synthesized that is soluble in both chloroform and water. This guest is able to bind to urea–adamantyl‐modified poly(propylene imine) dendrimers in chloroform in a noncovalent manner. When the chloroform is slowly evaporated and D2O is added, the hydrophobic dendrimer is solubilized in water. This is not possible when the hydrophobic dendrimer is directly added to the hydrophilic guests in water. When the unmodified poly(ethylene glycol) starting material is used, no solubilization occurs, and this indicates that the urea–acetic acid head group is necessary to solubilize the dendrimer. Approximately 26 guests are required for solubilization of the dendrimer. A lower number of guests results in aggregation and precipitation of the dendrimer. A monodisperse guest molecule has been used in NMR studies to show that the guest molecule binds with its acidic head group to the periphery of the dendrimer. This methodology opens the way to functional dendrimer aggregates in aqueous media. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 6431–6437, 2005