Aza-Residue Modulation of Cyclic d,l‑α-Peptide Nanotube Assembly with Enhanced Anti-Amyloidogenic Activity

Transient soluble oligomers of amyloid-β (Aβ)
are considered
among the most toxic species in Alzheimer’s disease (AD). Soluble
Aβ oligomers accumulate early prior to insoluble plaque formation
and cognitive impairment. The cyclic d,l-α-peptide
CP-2 (1) self-assembles into nanotubes and demonstrates
promising anti-amyloidogenic activity likely by a mechanism involving
engagement of soluble oligomers. Systematic replacement of the residues
in peptide 1 with aza-amino acid counterparts was performed
to explore the effects of hydrogen bonding on propensity to mitigate
Aβ aggregation and toxicity. Certain azapeptides exhibited improved
ability to engage, alter the secondary structure, and inhibit aggregation
of Aβ. Moreover, certain azapeptides disassembled preformed
Aβ fibrils and protected cells from Aβ-mediated toxicity.
Substitution of the l-norleucine3 and d-serine6 residues in peptide 1 with aza-norleucine
and aza-homoserine provided, respectively, nontoxic [azaNle3]-1 (4) and [azaHse6]-1 (7), that significantly abated symptoms in
a transgenic Caenorhabditis elegans AD model by decreasing Aβ oligomer levels.