Design of nonapeptide LVFFARKHH: A bifunctional agent against Cu -mediated amyloid β-protein aggregation and cytotoxicity.

J Mol Recognit

Department of Biochemical Engineering and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, China.

Published: June 2018

Dysfunctional accumulation of amyloid β-protein (Aβ) mediated by Cu exhibits higher neurotoxicity and accelerates the progress of Alzheimer's disease, so inhibition of Cu -mediated Aβ aggregation and cytotoxicity has been considered as a therapeutic strategy for the disease. Herein, a nonapeptide was designed by linking HH to the C-terminus of a peptide inhibitor of Aβ aggregation, LVFFARK (LK7). We found that the nonapeptide, LK7-HH, possessed dual functionality, including enhanced inhibition capability on Aβ aggregation as compared to LK7, and chelating Cu with a dissociation constant of 5.50 μM. This enabled LK7-HH to arrest the generation of reactive oxygen species catalyzed by Cu or Cu -Aβ complex, and to inhibit Cu -induced Aβ aggregation. Moreover, in contrast with the cytotoxicity of LK7 aggregates, LK7-HH was biocompatible because HH conjugation made its aggregation behavior different from LK7. Thus, LK7-HH efficiently suppressed Cu -mediated Aβ aggregation and cytotoxicity. An equimolar concentration of LK7-HH increased cell viability from 50% to 90% when treating Aβ -Cu complexes. The results provided insights into the roles of HH in enhancing the inhibition of Aβ and Cu -induced Aβ aggregations, in eliminating Cu -induced cytotoxicities by arresting generation of reactive oxygen species, and in making the peptide biocompatible. Therefore, this work would contribute to the design of potent peptide-based inhibitors of Cu -mediated Aβ aggregation and cytotoxicity.

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http://dx.doi.org/10.1002/jmr.2697DOI Listing

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