Amyloid fibril formation is assumed to be the molecular basis for a variety of diseases of unrelated origin. Despite its fundamental clinical importance, the mechanism of amyloid formation is not fully understood. When we analyzed a variety of short functional fragments from unrelated amyloid‐forming proteins, a remarkable occurrence of aromatic residues was observed. The finding of aromatic residues in diverse fragments raises the possibility that IT‐IT interactions may play a significant role in the molecular recognition and self‐assembly processes that lead to amyloid formation. This is in line with the well‐known central role of π‐stacking interactions in self‐assembly processes in the fields of chemistry and biochemistry. We speculate that the stacking interactions may provide energetic contribution as well as order and directionality in the self‐assembly of amyloid structures. Experimental data regarding amyloid formation and inhibition by short peptide analogs also support our hypothesis. The π‐stacking hypothesis suggests a new approach to understanding the self‐assembly mechanism that governs amyloid formation and indicates possible ways to control this process.—Gazit, E. A possible role for π‐stacking in the self‐assembly of amyloid fibrils. FASEB J. 16, 77–83 (2002)

In this tutorial review the process and applications of peptide self-assembly into nanotubes, nanospheres, nanofibrils, nanotapes, and other ordered structures at the nano-scale are discussed. The formation of well-ordered nanostructures by a process of self-association represents the essence of modern nanotechnology. Such self-assembled structures can be formed by a variety of building blocks, both organic and inorganic. Of the organic building blocks, peptides are among the most useful ones. Peptides possess the biocompatibility and chemical diversity that are found in proteins, yet they are much more stable and robust and can be readily synthesized on a large scale. Short peptides can spontaneously associate to form nanotubes, nanospheres, nanofibrils, nanotapes, and other ordered structures at the nano-scale. Peptides can also form macroscopic assemblies such as hydrogels with nano-scale order. The application of peptide building blocks in biosensors, tissue engineering, and the development of antibacterial agents has already been demonstrated.

The formation of well‐ordered fibrillar protein deposits is common to a large group of amyloid‐associated disorders. This group consists of several major human diseases such as Alzheimer's disease, Parkinson's disease, prion diseases, and type II diabetes. Currently, there is no approved therapeutic agent directed towards the formation of fibrillar assemblies, which have been recently shown to have a key role in the cytotoxic nature of amyloidogenic proteins. One important approach in the development of therapeutic agents is the use of small molecules that specifically and efficiently inhibit the aggregation process. Several small polyphenol molecules have been demonstrated to remarkably inhibit the formation of fibrillar assemblies in vitro and their associated cytotoxicity. Yet, the inhibition mechanism was mostly attributed to the antioxidative properties of these polyphenol compounds. Based on several observations demonstrating that polyphenols are capable of inhibiting amyloid fibril formation in vitro, regardless of oxidative conditions, and in view of their structural similarities we suggest an additional mechanism of action. This mechanism is assuming structural constraints and specific aromatic interactions, which direct polyphenol inhibitors to the amyloidogenic core. This proposed mechanism is highly relevant for future de novo inhibitors‘ design as therapeutic agents for the treatment of amyloid‐associated diseases.

Bio-inspired nano-materials can be formed by the ordered assembly of elementary building blocks. These peptide nanostructures can be utilized in many applications in various fields ranging from energy storage devices to drug delivery agents.

Amyloid diseases are global epidemics with profound health, social and economic implications and yet remain without a cure.