Peptide-Based Molecular Strategies To Interfere with Protein Misfolding, Aggregation, and Cell Degeneration

Protein misfolding into amyloid fibrils is linked to more than 40 as yet incurable cell- and neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and type 2 diabetes. So far, however, only one of the numerous anti-amyloid molecules has reached patients. This Minireview gives an overview of molecular strategies and peptide chemistry “tools” to design, develop, and discover peptide-based molecules as anti-amyloid drug candidates. We focus on two major inhibitor rational design strategies: 1) the oldest and most common strategy, based on molecular recognition elements of amyloid self-assembly, and 2) a more recent approach, based on cross-amyloid interactions. We discuss why peptide-based amyloid inhibitors, in particular their advanced generations, can be promising leads or candidates for anti-amyloid drugs as well as valuable tools for deciphering amyloid-mediated cell damage and its link to disease pathogenesis.