Aza-Residue Modulation of Cyclic D,L-alpha-Peptide Nanotube Assembly with Enhanced Anti-Amyloidogenic Activity

Transient soluble oligomers of amyloid-beta (A beta) are considered among the most toxic species in Alzheimer's disease (AD). Soluble A beta oligomers accumulate early prior to insoluble plaque formation and cognitive impairment. The cyclic D,L-alpha- 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 A beta aggregation and toxicity. Certain azapeptides exhibited improved ability to engage, alter the secondary structure, and inhibit aggregation of A beta. Moreover, certain azapeptides disassembled preformed A beta fibrils and protected cells from A beta-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 A beta oligomer levels.