z-logo
Premium
P4–300: N–methylated peptide inhibitors of β–amyloid aggregation
Author(s) -
Doig Andrew,
Kokkoni Nicoleta,
Stott Kelvin,
Amijee Hozefa,
Bottomley Joanna,
Mason Jody,
Treherne Mark,
Scopes David
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.2039
Subject(s) - chemistry , peptide , thioflavin , amyloid (mycology) , biochemistry , small molecule , in vitro , stereochemistry , oligomer , alzheimer's disease , organic chemistry , medicine , inorganic chemistry , disease , pathology
Background: The key pathogenic event in the onset of Alzheimer’s disease (AD) is believed to be the aggregation of the β-amyloid peptide (Aβ) into toxic oligomers. Molecules that interfere with this process may therefore act as therapeutic agents for the treatment of AD. N-methylated peptides (meptides) are a general class of peptide aggregation inhibitors that act by binding to one face of the aggregating peptide, but are unable to hydrogen bond on the other face, due to the N-methyl group. Objective(s): We optimized the structure of meptide inhibitors of Aβ aggregation, starting with the KLVFF lead sequence that is known to bind to Aβ. We varied the meptide length, N-methylation sites, acetylation and amidation of the N- and C-termini, side chain identity and chirality, via five compound libraries. Methods: Inhibitor activity was tested by Thioflavin T binding, affinity chromatography, electron microscopy and toxicity assays. Results: Optimized inhibitors were able to reverse the toxic effects of β-amyloid at nanomolar concentration on an in vitro brain slice, determined by long term potentiation. Related non-N-methylated analogues were insoluble and toxic. Light scattering and electron microscopy data suggest that the inhibitors act by inducing Aβ oligomers to aggregate into a non-toxic conformation. Conclusions: We found more potent compounds than all other known peptides, peptidomimetics and small molecule inhibitors

This content is not available in your region!

Continue researching here.

Having issues? You can contact us here