Conformational restriction via cyclization in β-amyloid peptide Aβ(1-28) leads to an inhibitor of Aβ(1-28) amyloidogenesis and cytotoxicity

Aphrodite Kapurniotu, Andreas Buck, Marco Weber, Anke Schmauder, Thomas Hirsch, Jürgen Bernhagen, Marianna Tatarek-Nossol

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

The aggregation process of β-amyloid peptide Aβ into amyloid is strongly associated with the pathology of Alzheimer's disease (AD). Aggregation may involve a transition of an α helix in Aβ(1-28) into β sheets and interactions between residues 18-20 of the "Aβ amyloid core." We applied an i, i+4 cyclic conformational constraint to the Aβ amyloid core and devised side chain-to-side chain lactam-bridged cyclo17, 21-[Lys17, Asp21]Aβ(1-28). In contrast to Aβ(1-28) and [Lys17, Asp21]Aβ(1-28), cyclo17, 21-[Lys17, Asp21]Aβ(1-28) was not able to form β sheets and cytotoxic amyloid aggregates. Cyclo17, 21-[Lys17, Asp21]Aβ(1-28) was able to interact with Aβ(1-28) and to inhibit amyloid formation and cytotoxicity. Cyclo17, 21-[Lys17, Asp21]Aβ(1-28) also interacted with Aβ(1-40) and interfered with its amyloidogenesis. Cyclo17, 21-[Lys17, Asp21]Aβ(1-28) or similarly constrained Aβ sequences may find therapeutic and diagnostic applications in AD.

Original languageEnglish
Pages (from-to)149-159
Number of pages11
JournalChemistry and Biology
Volume10
Issue number2
DOIs
StatePublished - 1 Feb 2003
Externally publishedYes

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