A Focused Chiral Mutant Library of the Amyloid β 42 Central Electrostatic Cluster as a Tool To Stabilize Aggregation Intermediates.

Amyloidogenic peptides and proteins aggregate into fibrillary structures that are usually deposited in tissues and organs, and are often involved in the development of diseases. In contrast to native structured proteins, amyloids do not follow a defined energy landscape towards the fibrillary state, and often generate a vast population of aggregation intermediates that are transient and exceedingly difficult to study. Here, we employ chiral editing as a tool to study the aggregation mechanism of the Amyloid β (Aβ) 42 peptide, whose aggregation intermediates are thought to be one of the main driving forces in Alzheimer’s disease (AD). Through the design of a focused chiral mutant library (FCML) of 16 chiral Aβ42 variants, we identified several point D-substitutions that allowed us to modulate the aggregation propensity and the biological activity of the peptide. Surprisingly, the reduced propensity towards aggregation and the stabilization of oligomeric intermediates did not always correlate with an increa...