Mechanistic Studies of the Process of Amyloid Fibrils Formation by the Use of Peptide Fragments and Analogues: Implications for the Design of Fibrillization Inhibitors

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Abstract:

The process of amyloid fibrils formation is a common mechanism of a large number of unrelated infectious, genetic and spontaneous diseases. A partial list includes the bovine spongiform encephalopathy (BSE), Alzheimer's diseases, Type II diabetes, Creutzfeldt-Jakob disease, and various unrelated amyloidosis diseases. In spite of its significant clinical importance, the mechanism of fibrillization is not fully understood. This review discusses the recent advancements in the mechanistic studies of amyloid formation by the use peptide fragments and analogues of amyloid-forming proteins and polypeptides. The use of short peptide shed much light of the mechanism of amyloid fibrillization. Recent studies clearly prove that very short peptide fragments (as short as pentapeptides) can form well-ordered amyloidal structures. Therefore, the molecular recognition and self-assembly process that lead to the formation of order structures is being mediated by small structural elements. Analysis of short amyloid-related fragment by the use of an alaninescan and sequence analysis of a variety of unrelated peptide and protein fragments suggest that aromatic interaction may play a central role in the process of amyloid formation. Inhibitors that are based on the short aromatic elements already demonstrated clear potency in arresting the process of amyloid fibrils formation. Taken together, the recent advancement in the mechanistic understanding of the process of amyloid fibrils formation has a major importance in the development of inhibitors of fibrillization that may serve as future therapeutic means to treat amyloid diseases.

Keywords: Amyloid formation; Islet amyloid polypeptide (IAPP); Protein misfolding; Type II diabetes

Document Type: Review Article

DOI: http://dx.doi.org/10.2174/0929867023369187

Publication date: October 1, 2002

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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