Figure 6.

Schematic diagram of macrocyclic peptides mimicking amyloidogenic protein self-association. Amyloid proteins are shown in light blue with amyloidogenic segments in pink. Mediated by amyloidogenic segments, an amyloidogenic protein forms transient and highly polymorphic oligomers, protofilaments and eventually mature fibers. By displaying the amyloidogenic peptides in the recognition strand of a macrocycle as a β-strand, the conformation of the peptides during self-assembly is mimicked. The Hao residue in the macrocyclic ring blocks the infinite molecular assembly and captures a single oligomeric state for X-ray crystallographic studies. The structures of the macrocycles reflect one very likely possibility for amyloid oligomer assembly. By mixing a macrocycle with an amyloidogenic protein, the β-strand mimics can interact with the same segment in the native protein. The Hao residue as a blocker may stop oligomers from further association into fibers and also cap protofilaments from elongation and maturation by binding at the growing edge of the sheets.