Peptide inhibitors of amyloid aggregation

Abstract

Amyloid aggregation is involved in the pathogenesis of various human diseases, primarily neurodegenerative, but also metabolic and other systemic diseases. Current therapies are mostly symptomatic treatments that do not address the underlying cause of the condition. To develop effective therapeutics, it is crucial to understand the mechanism of fibril formation. The amyloid fibrillation cascade is complex and involves three processes: primary nucleation, secondary nucleation, and elongation (with fragmentation). This process is characterized by a repertoire of intermediate states, which are potential targets for therapeutics. Special emphasis is placed on oligomeric and fibrillar forms, as they cause the most harm within the organism due to their toxicity. Studying the mechanism of amyloid formation common to various disease-related intrinsically disordered proteins is thus fundamental for therapeutics development and identifying novel diagnostic markers among these intermediate states. Consequently, biochemical studies of amyloid aggregation, particularly those monitoring kinetics and structure of aggregating species, are extensively conducted. Some of the most promising therapeutics for Alzheimer’s disease and similar amyloid-related conditions appear to be peptide-based, either antibodies designed to target specific states in the aggregation process, chaperones with broad substrate specificity and specific thermodynamic properties, or small peptides that facilitate drug delivery. In addition to novel therapeutic strategies, early diagnosis is crucial for addressing amyloid diseases. This paper gives an overview of the mechanism of amyloid formation common for different disease-related intrinsically disordered proteins, and the potential for peptide therapeutic development that arises from a mechanistic approach – monitoring aggregation kinetics.