D-amino acid-based peptide inhibitors as early or preventative therapy in Alzheimer disease

Abstract

Beta amyloid (Aβ) accumulation is recognized as a hallmark of Alzheimer disease (AD) pathology and the aggregation of Aβ peptide is hypothesized to drive pathogenesis. As such, Aβ is a logical target for therapeutic intervention and there have been many studies looking at diverse classes of drugs that target Aβ. Of concern is the recent failure of several clinical trials, highlighting the need for earlier, possibly preventative intervention, and raising the question of what form of Aβ is the best target. The Aβ oligomers are considered to be the toxic species, but many therapies, such as antibody therapies, target monomers, removing them as substrates for aggregation. Peptide inhibitors, in contrast, are able to interfere with the aggregation process itself. Designing peptide inhibitors requires some knowledge of Aβ structure; while there is structural information about the amyloid core of Aβ fibrils, the transient nature of oligomers makes them difficult to characterize. Fortunately, some interaction sites have been identified between monomers and oligomers of Aβ and these, plus known aggregation-prone sequences in Aβ, can serve as a basis for inhibitor design. In this mini-review we focus on D-amino acid based peptide inhibitors and discuss how their non-toxic and stable nature can be beneficial, while they specifically target aggregation-prone sequences within the Aβ peptide. Many peptide inhibitors have been designed using the LVFFA domain within Aβ to disrupt the self-assembly of Aβ peptide. While this may be sufficient to stop aggregation in vitro, other aggregation sites at the C-terminus may promote aggregation independently and the flexible N terminus may be a good target to induce clearance of aggregates. Ultimately, it may be a combination of targets that provides the best therapeutic strategy.

Figure 1. Schematic diagram of Aβ aggregation in the context of Alzheimer disease progression. The diagram is based on in vitro aggregation data and in vivo findings of Aβ plaque formation. The disease has a prolonged preclinical state, in which Aβ peptides undergo major structural transitions to form oligomers then fibrils. These fibrils undergo continuous fragmentation and reassembly during the course of the disease.

Figure 2. Aβ1–42 peptide showing monomer-oligomer interaction sites. (A) Aβ1–42 sequence. Monomeric Aβ has been shown to interact with oligomeric forms of Aβ at the residues indicated in red. (B) Three dimensional structure of Aβ1–42 based on liquid NMR. Interaction sites between monomer and oligomer are again displayed in red within the three dimensional monomer. (C) Three dimensional structure of amyloid Aβ1–42 based on solid state NMR, showing core region β sheet residues 17–42. The monomer-oligomer interaction sites are again shown in red with known hydrophobic interactions demonstrated as side chains. Residues 1–16 remain as a flexible N-terminus in this amyloid model and so the three N-terminal sites of oligomer interaction cannot be mapped onto this model. The remaining oligomer interaction sites are all within the amyloid core region, wih the highest correlation being between the two main aggregation motifs LVFFA and GxxxG.