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Design of β-Amyloid Aggregation Inhibitors from a Predicted Structural Motif

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† Department of Chemistry, Stanford University, Stanford, California 94305, United States
‡ Department of Neurology, UCLA, Los Angeles, California 90095, United States
§ Department of Pathology, Stanford University, Stanford, California 94305, United States
∥ Brain Research Institute, UCLA, Los Angeles, California 90095, United States
⊥ Molecular Biology Institute, UCLA, Los Angeles, California 90095, United States
*Phone: (650)723-3660. E-mail: [email protected]. Address: Department of Chemistry, Stanford University, 318 West Campus Drive, Stanford, California 94305.
Cite this: J. Med. Chem. 2012, 55, 7, 3002–3010
Publication Date (Web):March 15, 2012
https://doi.org/10.1021/jm201332p
Copyright © 2012 American Chemical Society
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    Abstract

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    Drug design studies targeting one of the primary toxic agents in Alzheimer’s disease, soluble oligomers of amyloid β-protein (Aβ), have been complicated by the rapid, heterogeneous aggregation of Aβ and the resulting difficulty to structurally characterize the peptide. To address this, we have developed [Nle35, d-Pro37]Aβ42, a substituted peptide inspired from molecular dynamics simulations which forms structures stable enough to be analyzed by NMR. We report herein that [Nle35, d-Pro37]Aβ42 stabilizes the trimer and prevents mature fibril and β-sheet formation. Further, [Nle35, d-Pro37]Aβ42 interacts with WT Aβ42 and reduces aggregation levels and fibril formation in mixtures. Using ligand-based drug design based on [Nle35, d-Pro37]Aβ42, a lead compound was identified with effects on inhibition similar to the peptide. The ability of [Nle35, d-Pro37]Aβ42 and the compound to inhibit the aggregation of Aβ42 provides a novel tool to study the structure of Aβ oligomers. More broadly, our data demonstrate how molecular dynamics simulation can guide experiment for further research into AD.

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    Results from experiments conducted with Aβscramble and [Sem35,d-Pro37]Aβ42. LC-MS and 1H NMR of 1, 2, and 3. Rankings and structures of top scoring compounds from the virtual screen. This material is available free of charge via the Internet at http://pubs.acs.org.

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