title: 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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan); ERATO (Japan) Science and Technology Agency (JST), Kanai Life Science Catalysis Project, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan).
authors.forename: Tadamasa
authors.initials: T
authors.lastname: Arai
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sasaki
authors.forename: Takushi
authors.initials: T
authors.lastname: Araya
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sato
authors.forename: Youhei
authors.initials: Y
authors.lastname: Sohma
authors.forename: Motomu
authors.initials: M
authors.lastname: Kanai
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D016716:PC12 Cells; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000494:pharmacology*; D066329:Protein Aggregates / Q000187:drug effects*; D066263:Protein Aggregation, Pathological / Q000188:drug therapy / Q000378:metabolism; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D010456:Peptides, Cyclic; D066329:Protein Aggregates
keywords: Alzheimer's disease; aggregation; amyloid beta-peptides; cyclic peptides; inhibitors