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

Abstract

Beta amyloid (ABβ) accumulation is recognized as a hallmark of Alzheimer disease (AD) pathology and the aggregation of A Bβ peptide is hypothesized to drive pathogenesis. As such, A Bβ is a logical target for therapeutic intervention and there have been many studies looking at diverse classes of drugs that target A Bβ. 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 A Bβ is the best target. The A Bβ 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 A Bβ structure; while there is structural information about the amyloid core of A Bβ fibrils, the transient nature of oligomers makes them difficult to characterize. Fortunately, some interaction sites have been identified between monomers and oligomers of A Bβ and these, plus known aggregation- prone sequences in A Bβ, 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 A Bβ peptide. Many peptide inhibitors have been designed using the LVFFA domain within A Bβ to disrupt the self-assembly of A Bβ 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. © 2014 Landes Bioscience.