Azacyclopeptide synthesis and their neuroprotective activity against Aβ toxicity
Protein misfolding and aggregation are the fundamental causes of amyloid diseases. Deposits of proteins in the form of amyloid fibrils and plaques are the characteristic features of more than twenty degenerative conditions, including Alzheimer’s, Parkinson’s, and Huntington’s diseases. Synthetic cyclic D,L-α-peptide nanotubes can mimic the structural and biochemical properties of amyloid proteins. The introduction of aza-residues into cyclic D,L-α-peptides was studied to enhance intermolecular hydrogen bonding between stacked rings within the tube structures. The resulting cyclic aza-D,L-α-peptides were also expected to exhibit enhanced propensity to interact with the sheet structures of amyloid oligomers.  The lead peptide CP-2 features the sequence [l-J-w-H-s-K] in which lower and upper-case letters indicate D- and L-amino acids, respectively, square brackets designate a cyclic structure, and J denotes norleucine. There are no reports for introduction of aza-residues into cyclic D,L-α-peptides. Considering the potential for semicarbazides to enhance intermolecular hydrogen bonding, we performed an aza-glycine scan of the CP-2 sequence by preparing a focused library of azapeptides. All the cyclic aza-glycine peptides were tested for neuroprotective activity against amyloid using cell viability assay (MTT assay). The aza-glycine replacing D-serine i.e., [azaG2]-CP-2 (4) was found to be more potent than CP-2. This is the first example of introducing an aza-amino residue into a cyclic D, L-α-peptide, and these results could be extrapolated to other cyclic D, L-α-peptides of therapeutic interest.
Azapeptides Amyloid Alzheimer’s disease Cyclic D L-α-peptides Tubular structures