Frontiers of Chemical Science and Engineering
>> 2018,
Volume 12,
Issue 2
doi:
10.1007/s11705-017-1687-2
RESEARCH ARTICLE
Head-to-tail cyclization of a heptapeptide eliminates its cytotoxicity and significantly increases its inhibition effect on amyloid
. Department of Biochemical Engineering and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China.. Department of Chemical and Biomolecular Engineering, The University of Akron, Akron, OH 44325, USA
Accepted: 2018-01-11
Available online: 2018-05-09
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Abstract
Amyloid- (A ) protein aggregation is the main hallmark of Alzheimer’s disease (AD). Inhibition of A fibrillation is thus a promising therapeutic approach to the prevention and treatment of AD. Recently, we designed a heptapeptide inhibitor, LVFFARK (LK7). LK7 shows a promising inhibitory capability on A fibrillation, but is prone to self-assembling and displays high cytotoxicity, which would hinder its practical application. Herein, we modified LK7 by a head-to-tail cyclization and obtained a cyclic LK7 (cLK7). cLK7 exhibits a different self-assembly behavior from LK7, and has higher stability against proteolysis than LK7 and little cytotoxicity to SH-SY5Y cells. Thermodynamic analysis revealed that both LK7 and cLK7 could bind to A by electrostatic interactions, hydrogen bonding and hydrophobic interactions, but the binding affinity of cLK7 for A ( = 4.96 µmol/L) is six times higher than that of LK7 ( = 32.2 µmol/L). The strong binding enables cLK7 to stabilize the secondary structure of A and potently inhibit its nucleation, fibrillation and cytotoxicity at extensive concentration range, whereas LK7 could only moderately inhibit A fibrillation and cytotoxicity at low concentrations. The findings indicate that the peptide cyclization is a promising approach to enhance the performance of peptide-based amyloid inhibitors.
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