A False Paradise - Mixed Blessings in the Protein Universe: The Amyloid as a New Challenge in Drug Development
Significant advances in therapeutic applications of proteins and peptides have brought new challenges in the field of drug development. Ordered protein aggregation known as amyloid formation has recently emerged as a universal phenomenon due to extensive research in protein folding and amyloid diseases. The amyloid represents a new generic structure characterized by cross-β-sheet formation in its core, which implies that any polypeptide can adopt this conformation under amyloid-prone conditions. Some widely-used biopharmaceuticals such as insulin, glucagon, amylin and calcitonin have been shown to form amyloids and this list may be significantly extended upon further research. Compared to soluble precursor proteins and amorphous aggregates amyloids gain new properties such as remarkable stability and protease resistance, polymorphism, selfpropagation via seeding and cross-seeding, cytotoxicity and induced immunogenicity. Some of them can be hazardous in biopharmaceutical applications. The causes of amyloid aggregation and strategies for its prevention are reviewed here. They utilize the current knowledge of amyloid properties, structure-based design principles and protein chemistry. Once these challenges are met, they will ultimately lead to safer and surer pharmaceuticals.
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Document Type: Research Article
Affiliations: Department of Medical Biochemistry and Biophysics, Umea University, SE-901 87 Umea, Sweden.
Publication date: 01 May 2007
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