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J Med Chem. 2011 Dec 22;54(24):8451-60. doi: 10.1021/jm200982p. Epub 2011 Nov 28.

C-terminal tetrapeptides inhibit Aβ42-induced neurotoxicity primarily through specific interaction at the N-terminus of Aβ42.

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Department of Neurology, David Geffen School of Medicine, Brain Research Institute, University of California, Los Angeles, 635 Charles E. Young Drive South, Los Angeles, California 90095-7334, United States.


Inhibition of amyloid β-protein (Aβ)-induced toxicity is a promising therapeutic strategy for Alzheimer's disease (AD). Previously, we reported that the C-terminal tetrapeptide Aβ(39-42) is a potent inhibitor of neurotoxicity caused by Aβ42, the form of Aβ most closely associated with AD. Here, initial structure-activity relationship studies identified key structural requirements, including chirality, side-chain structure, and a free N-terminus, which control Aβ(39-42) inhibitory activity. To elucidate the binding site(s) of Aβ(39-42) on Aβ42, we used intrinsic tyrosine (Y) fluorescence and solution-state NMR. The data suggest that Aβ(39-42) binds at several sites, of which the predominant one is located in the N-terminus of Aβ42, in agreement with recent modeling predictions. Thus, despite the small size of Aβ(39-42) and the hydrophobic, aliphatic nature of all four side-chains, the interaction of Aβ(39-42) with Aβ42 is controlled by specific intermolecular contacts requiring a combination of hydrophobic and electrostatic interactions and a particular stereochemistry.

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