Tripeptide GGH as the Inhibitor of Copper-Amyloid-β-Mediated Redox Reaction and Toxicity

Abstract

The Aβ complexes of some redox-active species, such as Cu, cause oxidative stress and induce severe toxicity by generating reactive oxygen species (ROS). Thus, Cu chelation therapy should be considered as a valuable strategy for the treatment of Alzheimer's disease (AD). However, more attention should be paid to the specific chelating ability of these chelating agents. Herein, a tripeptide GGH was used to selectively chelate the Cu(2+) in Aβ-Cu complex in the presence of other metal ions (e.g., K(+), Ca(2+), Ni(2+), Mg(2+), and Zn(2+)) as shown by isothermal titration calorimetry results. GGH decreased the level of HO(•) radicals by preventing the formation of intermediate Cu(I) ion. Thus, the Cu species completely lost its catalytic activity at a superequimolar GGH/Cu(II) ratio (4:1) as observed by UV-visible spectroscopy, coumarin-3-carboxylic acid fluorescence, and BCA assay. Moreover, (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay indicates that GGH increased PC-12 cell viability from 36% to 63%, and neurotoxicity partly triggered by ROS decreased. These results indicate potential development of peptide chelation therapy for AD treatment.

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

“…ITC experiments were performed at 37°C on a VP isothermal titration calorimeter (MicroCal, Northampton, MA, USA) in buffer A. Protein/peptide solution was placed in the sample cell and CuCl 2 solution at an appropriate concentration was loaded into the syringe injector. To ensure the solubility of Cu 2+ in buffer A, a certain amount of glycine (Gly) was added to the solution . After an initial delay of 800 seconds, 260‐μL Cu 2+ was titrated in 10‐μL increments at a constant interval of 300 seconds.…”

“…It has been known that peptides containing histidine (H) residues can coordinate with Cu 2+ through the N atom of imidazole group . For this reason, Aβ 12–20 and Aβ 13–20 were used as bifunctional peptides to inhibit the aggregation of Aβ‐Cu 2+ complexes .…”

A Trishistidine Pseudopeptide with Ability to Remove Both CuΙ and CuΙΙ from the Amyloid‐β Peptide and to Stop the Associated ROS Formation

“…[3d, 9a, 11, 13] for recent reviews), including with peptide-based ligands. [14] Only few studies have focused on Cu i synthetic chelators,[15] based on previous results using naturally occurring Cu i proteins. [16] The reason for such a preference is not clear and has no real biological basis since the extracellular space of brain where the senile plaques are observed mainly represents a reducing environment.…”

Activation Effects of Carnosine- and Histidine-Containing Dipeptides on Human Carbonic Anhydrases: A Comprehensive Study

“…Indeed and due to the satisfactory degree of conservation of the residues involved in the activator's binding site (see Figure GV1C), these resolved CA-II complexes can be used as a general platform to rationalize the obtained results for all the evaluated isoforms. In detail, docking simulations involved the resolved CA-II structure in complex with L-histidine (PDB Id: 2ABE), a known activator similar to those here considered [17]. The CA structure was prepared by removing water molecules (apart from that bound to zinc ion) and crystallization additives.…”

“…On these grounds, the present study was undertaken to systematically investigate the activating profiles of these histidine containing derivatives on a panel of representative human CA isozymes including hCA I, hCA II, hCA VA and hCA IX. As listed in Figure 1 and Table 1, the study comprised the above mentioned naturally occurring carnosine derivatives, two analogues including the non-natural D-His residue (i.e., d-carnosine [16] and d-carnosinamide), the tripeptide Gly-Gly-l-His, a well-known metal chelator [17], chosen here to investigate the capacity of enzymatic binding cavity to accommodate larger derivatives and finally a recently proposed synthetic analogue modified on the carboxyl group (i.e., l-carnosinol) [18]. The monitored bioactivities were finally rationalized by docking simulations involving the hCA II isozyme chosen due to the availability of resolved structures in complex with histidine [19].…”