Peptidomimetics That Inhibit and Partially Reverse the Aggregation of Aβ 1-42

The peptide sequence KLVFF resembles the hydrophobic core of the Aβ peptide known to form amyloid plaques in Alzheimer's disease. Starting from its retro-inverso peptide, we have synthesized three generations of peptidomimetics. Step by step natural amino acids have been replaced by aromatic bu...

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Bibliographic Details
Published in:Biochemistry (Easton) 2017-09, Vol.56 (36), p.4840-4849
Main Authors: Stark, Tina, Lieblein, Tobias, Pohland, Maximilian, Kalden, Elisabeth, Freund, Petra, Zangl, René, Grewal, Rekha, Heilemann, Mike, Eckert, Gunter P, Morgner, Nina, Göbel, Michael W
Format: Article
Language:English
Subjects:
Amyloid beta-Peptides
Cell Line
Cell Proliferation - drug effects
Cell Survival - drug effects
Humans
Lactate Dehydrogenases - genetics
Lactate Dehydrogenases - metabolism
Molecular Structure
Peptide Fragments - chemistry
Peptidomimetics - chemistry
Peptidomimetics - pharmacology
Protein Binding
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Summary:The peptide sequence KLVFF resembles the hydrophobic core of the Aβ peptide known to form amyloid plaques in Alzheimer's disease. Starting from its retro-inverso peptide, we have synthesized three generations of peptidomimetics. Step by step natural amino acids have been replaced by aromatic building blocks accessible from the Pd-catalyzed Catellani reaction. The final compound 18 is stable against proteolytic decay and largely prevents the aggregation of Aβ over extended periods of time. The activity of the new inhibitors was tested first by fluorescence correlation spectroscopy. For closer examination of compound 18, additional techniques were also applied: laser-induced liquid bead ion desorption mass spectrometry, confocal laser scanning microscopy, thioflavin T fluorescence, and gel electrophoresis. Compound 18 not only retards the aggregation of chemically synthesized Aβ but also can partially dissolve the oligomeric structures. Thioflavin binding mature fibrils, however, seem to resist the inhibitor.
ISSN:0006-2960
1520-4995
DOI:10.1021/acs.biochem.7b00223