Carnosine-LVFFARK-NH2 Conjugate: A Moderate Chelator but Potent Inhibitor of Cu2+-Mediated Amyloid β-Protein Aggregation

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Aggregation of amyloid-β (Aβ) protein stimulated by Cu2+ has been recognized as a crucial step in the neurodegenerative process of Alzheimer’s disease. Hence, it is of significance to develop bifunctional agents capable of inhibiting Aβ aggregation as well as Cu2+-mediated Aβ toxicity. Herein, a novel bifunctional nonapeptide, carnosine-LVFFARK-NH2 ( Car-LK7), was proposed by integrating native chelator carnosine ( Car) and an Aβ aggregation inhibitor, Ac-LVFFARK-NH2 (LK7). Results revealed the bifunctionality of Car-LK7, including remarkably enhanced inhibition capability on Aβ aggregation as compared to LK7 and a moderate Cu2+ chelating affinity ( KD = 28.2 ± 2.1 μM) in comparison to the binding affinity for Aβ40 ( KD = 1.02 ± 0.13 μM). The moderate Cu2+ affinity was insufficient for Car-LK7 to sequester Cu2+ from Aβ40-Cu2+ species, but it was sufficient to form ternary Aβ40-Cu2+- Car-LK7 complexes. Formation of the ternary complexes directed the aggregation into small, unstructured aggregates with little β-sheet structure. Car-LK7 also showed higher activity on arresting Aβ40-Cu2+-catalyzed reactive oxygen species production than Car. Cell viability assays confirmed the prominent protection activity of Car-LK7 against Cu2+-mediated Aβ40 cytotoxicity; Car-LK7 could almost eliminate Aβ40 cytotoxicity at an equimolar dose (cell viability increased from 59% to 99%). The research has thus provided new insight into the design of potent bifunctional agents against metal-mediated amyloid toxicity by conjugating moderate metal chelators and existing inhibitors. (ACS Chem Neurosci. 2018 Nov 21;9(11):2689-2700.)

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