A Cyclic KLVFF‐Derived Peptide Aggregation Inhibitor Induces the Formation of Less‐Toxic Off‐Pathway Amyloid‐β Oligomers

Abstract

Inhibition of amyloid-β (Aβ) aggregation could be a target of drug development for the treatment of currently incurable Alzheimer's disease. We previously reported that a head-to-tail cyclic peptide of KLVFF (cyclic-KLVFF), a pentapeptide fragment corresponding to the Aβ16-20 region (which plays a critical role in the generating Aβ fibrils), possesses potent inhibitory activity against Aβ aggregation. Here we found that the inhibitory activity of cyclic-KLVFF was significantly improved by incorporating an additional phenyl group at the β-position of the Phe4 side chain (inhibitor 3). Biophysical and biochemical analyses revealed the rapid formation of 3-embedded oligomer species when Aβ1-42 was mixed with 3. The oligomer species is an "off-pathway" species with low affinity for cross-β-sheet-specific dye thioflavin T and oligomer-specific A11 antibodies. The oligomer species had a sub-nanometer height and little capability of aggregation to amyloid fibrils. Importantly, the toxicity of the oligomer species was significantly lower than that of native Aβ oligomers. These insights will be useful for further refinement of cyclic-KLVFF-based aggregation inhibitors.

Modulation of prion polymerization and toxicity by rationally designed peptidomimetics

“…Apparently, these large oligomers were energetically disfavored, which collapsed later and receded into unordered aggregates with time ( Figure 1I). Formation of these unordered aggregates indicates an off-pathway modulation, similar to the effect of resveratrol and cyclic KLVFF-derived peptide on Aβ amyloidogenesis [76,108]. PrP Sc reportedly exists in an oligomeric and membrane-associated form and its accumulation compromises fundamental membrane functions [8].…”

Peptidomimetics prepared by tail-to-side chain one component peptide stapling inhibit Alzheimer's amyloid-β fibrillogenesis

“…The offpathway oligomers correspond to non-toxic species that cannot progress to toxic amyloid brils, thereby preventing the native aggregation pathway. 33 However, further investigations are required to understand the mechanism better.…”

Inhibitors of protein aggregates as novel drugs in neurodegenerative diseases

“…This region, known as the KLVFFA, is an hexapeptide sequence that facilitates monomer-monomer interaction, leading to dimer and oligomer formation [48,49]. Based on these findings, a few compounds have been identified and demonstrated to interact with the KLVFFA region [50].…”