A Cyclic KLVFF‐Derived Peptide Aggregation Inhibitor Induces the Formation of Less‐Toxic Off‐Pathway Amyloid‐β Oligomers. Issue 17 (26th September 2014)

• Record Type: Journal Article
• Authors: Arai, Tadamasa; Sasaki, Daisuke; Araya, Takushi; Sato, Takeshi; Sohma, Youhei; Kanai, Motomu
• Is Part Of: Chembiochem. Volume 15:Issue 17(2014)
• Page Start: 2577
• Page End: 2583
• Publication Date: 2014-09-26
• Subjects: Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201402430
• Languages: English
• ISSNs: 1439-4227

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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 <bold>3</bold>). Biophysical and biochemical analyses revealed the rapid formation of <bold>3</bold>‐embedded oligomer species when Aβ1–42 was mixed with <bold>3</bold>. 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.</p> </abstract>