Synthesis and study of macrocyclic β-hairpin peptides for investigating amyloid oligomers

Chemically constrained peptides that self-assemble can be used to better understand the molecular basis of amyloid diseases. The formation of small assemblies of the amyloidogenic peptides and proteins, termed oligomers, is central to amyloid diseases. The use of chemical model systems can help provide insights into the structures and interactions of amyloid oligomers, which are otherwise difficult to study. This chapter describes the use of macrocyclic β-hairpin peptides as model systems to study amyloid oligomers. The first part of the chapter describes the chemical synthesis of the macrocyclic β-hairpin peptides and covalent assemblies thereof. The second part of the chapter describes the characterization of the oligomers formed by the macrocyclic β-hairpin peptides, focusing on SDS-PAGE, size-exclusion chromatography (SEC), and X-ray crystallography. The procedures provided focus on the β-amyloid peptide, but these strategies are applicable to a broad range of amyloid-derived peptides and proteins.