A False Paradise - Mixed Blessings in the Protein Universe: The Amyloid as a New Challenge in Drug Development

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-beta-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, self-propagation 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.

Lability Landscape and Protease Resistance of Human Insulin Amyloid: A New Insight into Its Molecular Properties

“…[31][32][33][34][35][36][37][38][39][40][41][42][43][44] Here, we demonstrate that the stability and lability of insulin amyloid are strongly pH dependent and, therefore, can be prevented and tightly controlled during the insulin production and application processes. A focus in the amyloid field concerns how amyloid depositions can be triggered and propagated in the body.…”

“…[31][32][33][34][35][36][37][38][39] The formation of insoluble insulin aggregates can lead to a significant reduction of the functionally active substance in formulations, posing serious problems in biopharmaceutical applications. [40][41][42][43][44] Regular injections of insulin can also cause long-term effects, such as depositions of insulin amyloid, which have been observed in diabetic patients after repeated injections. [45][46][47] In our studies, we produced insulin amyloids in the absence of Zn 2+ ions and under low pH conditions where the protein exists in the destabilized monomeric state.…”

High productivity of human recombinant beta-interferon from a low-temperature perfusion culture

“…Protein aggregation can be a problem in both the production and subsequent shelf-life of biopharmaceuticals (Morozova-Roche and Malisauskas, 2007;Roberts et al, 2003). The design of a bioprocess for high productivity of ␤-IFN is a challenge because of its hydrophobicity and its tendency to aggregate in culture medium.…”

Structural Origin of ELOA Toxicity – Implication for HAMLET-Type Protein Complexes with Oleic Acid

“…Amyloid oligomers attracted particular attention among protein self-assembled complexes due to their critical involvement in several amyloid and conformational diseases [25][26][27]. Oligomerisation precedes the amyloid fibril formation and oligomers may serve as nuclei for fibrillar growth.…”