This title appears in the Scientific Report :
2020
Please use the identifier:
http://hdl.handle.net/2128/26813 in citations.
Please use the identifier: http://dx.doi.org/10.1016/j.bioorg.2020.104012 in citations.
β-Turn mimetic synthetic peptides as amyloid-β aggregation inhibitors
β-Turn mimetic synthetic peptides as amyloid-β aggregation inhibitors
Aggregation of amyloid peptides results in severe neurodegenerative diseases. While the fibril structures of Aβ40and Aβ42 have been described recently, resolution of the aggregation pathway and evaluation of potent inhibitorsstill remains elusive, in particular in view of the hairpin-region of Aβ40....
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Personal Name(s): | Deike, Stefanie |
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Rothemund, Sven / Voigt, Bruno / Samantray, Suman / Strodel, Birgit / Binder, Wolfgang H. (Corresponding author) | |
Contributing Institute: |
Strukturbiochemie; IBI-7 |
Published in: | Bioorganic chemistry, 101 (2020) S. 104012 - |
Imprint: |
San Diego, Calif.
Elsevier
2020
|
DOI: |
10.1016/j.bioorg.2020.104012 |
Document Type: |
Journal Article |
Research Program: |
Physical Basis of Diseases |
Link: |
OpenAccess |
Publikationsportal JuSER |
Please use the identifier: http://dx.doi.org/10.1016/j.bioorg.2020.104012 in citations.
Aggregation of amyloid peptides results in severe neurodegenerative diseases. While the fibril structures of Aβ40and Aβ42 have been described recently, resolution of the aggregation pathway and evaluation of potent inhibitorsstill remains elusive, in particular in view of the hairpin-region of Aβ40. We here report the preparationof beta-turn mimetic conjugates containing synthetic turn mimetic structures in the turn region of Aβ40 and Aβ16-35, replacing 2 amino acids in the turn-region G25 – K28. The structure of the turn mimic induces both, accelerationof fibrillation and the complete inhibition of fibrillation, confirming the importance of the turn regionon the aggregation. Replacing position G25-S26 provided the best inhibition effect for both beta-turn mimetics,the bicyclic BTD 1 and the aromatic TAA 2, while positions N27-K28 and V24-G25 showed only weaker or noinhibitory effects. When comparing different turn mimetics at the same position (G25-S26), conjugate 1a bearingthe BTD turn showed the best inhibition of Aβ40 aggregation, while 5-amino-valeric acid 4a showed the weakesteffect. Thus there is a pronounced impact on fibrillation with the chemical nature of the embedded beta-turnmimic:the conformationally constrained turns 1 and 2 lead to a significantly reduced fibrillation, even inhibitingfibrillation of native Aβ40 when added in amounts down to 1/10, whereas the more flexible beta-turn-mimics 4-amino-benzoic acid 3a and 5-amino-valeric acid 4a lead to enhanced fibrillation. Toxicity-testing of the mostsuccessful conjugate showed only minor toxicity in cell-viability assays using the N2a cell line. Structuraldownsizing lead to the short fragment BTD/peptide Aβ16-35 as inhibitor of the aggregation of Aβ40, opening largepotential for further small peptide based inhibitors. |