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

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 cyclo^{17, 21}-[Lys¹⁷, Asp²¹]Aβ(1-28). In contrast to Aβ(1-28) and [Lys¹⁷, Asp²¹]Aβ(1-28), cyclo^{17, 21}-[Lys¹⁷, Asp²¹]Aβ(1-28) was not able to form β sheets and cytotoxic amyloid aggregates. Cyclo^{17, 21}-[Lys¹⁷, Asp²¹]Aβ(1-28) was able to interact with Aβ(1-28) and to inhibit amyloid formation and cytotoxicity. Cyclo^{17, 21}-[Lys¹⁷, Asp²¹]Aβ(1-28) also interacted with Aβ(1-40) and interfered with its amyloidogenesis. Cyclo^{17, 21}-[Lys¹⁷, Asp²¹]Aβ(1-28) or similarly constrained Aβ sequences may find therapeutic and diagnostic applications in AD.