Design of nonapeptide LVFFARKHH: A bifunctional agent against Cu²⁺‐mediated amyloid β‐protein aggregation and cytotoxicity

Abstract

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.

Interactions between Curcumin Derivatives and Amyloid-β Fibrils: Insights from Molecular Dynamics Simulations

“…Computational methods have been used to provide insights into molecular docking, 22 , 23 , 52 , 102 , 103 drug discovery, 16 − 20 , 94 and amyloid formation 104 − 130 and inhibition. 27 , 36 , 37 , 86 , 82 , 131 − 149 The thermodynamics of Aβ fibril elongation and dissociation was also investigated in the absence of any molecules, providing outstanding insights into the atomistic origins of the Arrhenius barriers.…”

Self-triggered click reaction in an Alzheimer's disease model:in situbifunctional drug synthesis catalyzed by neurotoxic copper accumulated in amyloid-β plaques

“…Spectral titration 6 and isothermal titration calorimetry (ITC) experiments [65][66][67] were carried out to measure the binding stoichiometry (n) and binding affinity of compound 6 with Cu. Aer adding CuCl 2 , the absorbance of compound 6 at 321 nm was slightly decreased (Fig.…”

“…The affinity of compound 6 to Cu was appropriate to disrupt Ab-Cu interaction (Table S1 †), without affecting the normal function of the metal enzymes. 67 The binding affinity between compound 5 and Cu was too low to detect by ITC, showing that propargylglycine and glycine have equivalent chelating ability to Cu. We then assessed the ability of compound 6 to photooxygenate Ab and inhibit its aggregation.…”

“…The apparent binding constant (K a ), binding enthalpy (DH), and binding stoichiometry (n) were determined by tting ITC data following information from the literature without considering the competing effects of glycine with Cu 2+ . 66,67 When Cu 2+ -glycine was taken into consideration, the K a values of Cu to Ab and compound 6 were 1.63 Â 10 9 M À1 and 1.04 Â 10 10 M À1 , respectively. 65…”

Computational design and evaluation of β‐sheet breaker peptides for destabilizing Alzheimer's amyloid‐β42 protofibrils

“…6,7 One of the most useful strategies to interfere with Aβ 42 aggregation has been the design and use of peptides homologous to the Aβ 42 sequence; as Aβ 42 sequencebased peptides possess self-recognition property. [8][9][10][11] The peptide inhibitors based on the Aβ 42 sequence bind to the complementary parent sequence in full-length Aβ 42 and block the binding of additional Aβ 42 peptides, thus interfering with the aggregation process. However, none of the peptides based on the Aβ 42 parent sequence efficiently inhibited Aβ 42 aggregation or destabilized Aβ 42 protofibril structure.…”