Development of retro-inverso peptides as anti-aggregation drugs for β-amyloid in Alzheimer's disease

Alzheimer's disease (AD) is a devastating degenerative disorder of the brain for which there is no cure or effective treatment. There is much evidence to suggest that β-amyloid protein (Aβ) aggregation in the brain leading to deposits is an important step in the development of AD. Recently, two peptides, RGKLVFFGR (OR1) and RGKLVFFGR–NH2 (OR2) containing the sequence KLVFF, which is the central region (residues 16–20) of Aβ, have been found to be potent inhibitors of Aβ aggregate formation. Here we report that retro-inversion of these sequences increases efficacy of the peptides in the inhibition of aggregation and toxicity of β-amyloid. We describe the synthesis and inhibitory properties of these retro-inverso peptides.

Research highlights▶ Oligomeric forms of the peptide, β-amyloid, are known to damage neurons and to inhibit synaptic plasticity, leading to the cognitive decline in Alzheimer's disease. ▶ Synthetic peptides containing a retroinversion of residues 16–22 of β-amyloid have been synthesized. ▶ The retroinverted peptides were found to be more potent than native 16–22 peptides in preventing soluble oligomer and fibril formation from β-amyloid 40 and β-amyloid 42. ▶ The retroinverted peptides have higher efficacy at blocking the neurotoxicity of β-amyloid in human neuroblastoma cell cultures. ▶ As the retroinverted peptides prevent formation of both β-amyloid oligomers and fibrils, oligomers and fibrils are likely to be on the same biosynthetic pathway.