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

作者：Arai Tadamasa; Sasaki Daisuke; Araya Takushi; Sato Takeshi; Sohma Youhei^*; Kanai Motomu

来源：ChemBioChem, 2014, 15(17): 2577-2583.

DOI：10.1002/cbic.201402430

• aggregation
• Alzheimer's disease
• amyloid beta-peptides
• cyclic peptides
• inhibitors

Inhibition of amyloid-beta (A beta) 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 A beta 16-20 region (which plays a critical role in the generating A beta fibrils), possesses potent inhibitory activity against A beta aggregation. Here we found that the inhibitory activity of cyclic-KLVFF was significantly improved by incorporating an additional phenyl group at the beta-position of the Phe4 side chain (inhibitor 3). Biophysical and biochemical analyses revealed the rapid formation of 3-embedded oligomer species when A beta 1-42 was mixed with 3. The oligomer species is an "off-pathway" species with low affinity for cross-beta-sheetspecific 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 A beta oligomers. These insights will be useful for further refinement of cyclic-KLVFF-based aggregation inhibitors.

• 出版日期2014-11-24