Abstract
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.
Keywords: amyloid, nucleation, cross-seeding, cytotoxicity, inhibitors, lysozyme, biopharmaceuticals
Current Medicinal Chemistry
Title: A False Paradise - Mixed Blessings in the Protein Universe: The Amyloid as a New Challenge in Drug Development
Volume: 14 Issue: 11
Author(s): Ludmilla Morozova-Roche and Mantas Malisauskas
Affiliation:
Keywords: amyloid, nucleation, cross-seeding, cytotoxicity, inhibitors, lysozyme, biopharmaceuticals
Abstract: 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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Morozova-Roche Ludmilla and Malisauskas Mantas, A False Paradise - Mixed Blessings in the Protein Universe: The Amyloid as a New Challenge in Drug Development, Current Medicinal Chemistry 2007; 14 (11) . https://dx.doi.org/10.2174/092986707780597989
DOI https://dx.doi.org/10.2174/092986707780597989 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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