A simple dipeptide self‐assembles into a biocompatible hydrogel (see figure and inside cover). This novel biomaterial is extremely simple to prepare and has a remarkable rigidity. It is very stable under extreme conditions, can be injected, and can be shaped according to the vessel it has been assembled in. The hydrogel allows a wide variety of possible biomedical applications including tissue engineering, axonal regeneration, and controlled drug release.

Gaining insight into the mechanism of amyloid fibril formation, the hallmark of multiple degenerative syndromes of unrelated origin, and exploring novel directions of inhibition are crucial for preventing disease development. Specific interactions between aromatic moieties were suggested to have a key role in the recognition and self-assembly processes leading to the formation of amyloid fibrils by several amyloidogenic polypeptides, including the beta-amyloid polypeptide associated with Alzheimer's disease. Our finding of the high-affinity molecular recognition and intense amyloidogenic potential of tryptophan-containing peptide fragments led to the hypothesis that screening for indole derivatives might lead to the identification of potential inhibitors of amyloid formation. Such inhibitors could mediate specific recognition processes without allowing further growth of the well-ordered amyloid chain. Using fluorescence spectroscopy, atomic force microscopy, and electron microscopy to screen 29 indole derivatives, we identified three potent inhibitors: indole-3-carbinol (I3C), 3-hydroxyindole (3HI), and 4-hydroxyindole (4HI). The latter, a simple low-molecular weight aromatic compound, was the most effective, completely abrogating not only the formation of aggregated structures by Abeta but also the cytotoxic activity of aggregated Abeta toward cultured cells. The results of this study provide further experimental support for the paradigm of amyloid inhibition by heteroaromatic interaction and point to indole derivatives as a simple molecular platform for the development of novel fibrillization inhibitors.

A rationally designed oligomerization inhibitor interacts with early intermediate assemblies of amyloid-beta polypeptide (Abeta) through the aromatic elements and inhibits their assembly into the toxic oligomers that cause Alzheimer's disease by a unique C(alpha)-methylation beta-breakage strategy. The electrostatic potential of the low-energy conformation of the dipeptide inhibitor bound to Abeta is shown.

Ein gezielt entworfener Oligomerisierungshemmer wechselwirkt mit frühen intermediären Aβ‐Aggregaten (Aβ=Amyloid‐β‐Polypeptid) und inhibiert so die Bildung der toxischen Oligomere, die die Alzheimer‐Krankheit verursachen. Das Bild zeigt das elektrostatische Potential der niederenergetischen Konformation des Dipeptid‐Inhibitors im Komplex mit Aβ.

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