Designed Metal-ATCUN Derivatives: Redox- and Non-redox-Based Applications Relevant for Chemistry, Biology, and Medicine

Abstract

Summary The designed “ATCUN” motif (amino-terminal copper and nickel binding site) is a replica of naturally occurring ATCUN site found in many proteins/peptides, and an attractive platform for multiple applications, which include nucleases, proteases, spectroscopic probes, imaging, and small molecule activation. ATCUN motifs are engineered at periphery by conjugation to recombinant proteins, peptides, fluorophores, or recognition domains through chemically or genetically, fulfilling the needs of various biological relevance and a wide range of practical usages. This chemistry has witnessed significant growth over the last few decades and several interesting ATCUN derivatives have been described. The redox role of the ATCUN moieties is also an important aspect to be considered. The redox potential of designed M-ATCUN derivatives is modulated by judicious choice of amino acid (including stereochemistry, charge, and position) that ultimately leads to the catalytic efficiency. In this context, a wide range of M-ATCUN derivatives have been designed purposefully for various redox- and non-redox-based applications, including spectroscopic probes, target-based catalytic metallodrugs, inhibition of amyloid-β toxicity, and telomere shortening, enzyme inactivation, biomolecules stitching or modification, next-generation antibiotic, and small molecule activation.

A Deeper Insight in Metal Binding to the hCtr1 N-terminus Fragment: Affinity, Speciation and Binding Mode of Binuclear Cu2+ and Mononuclear Ag+ Complex Species

“…The oxidation kinetics of ascorbate has been extensively investigated employing both free Cu 2+ and Cu 2+ complexes [ 43 ]; these data show that the different Cu 2+ binding environments drive the kinetics and mechanisms of the ascorbate oxidation. Some studies report that different Cu 2+ binding domains in the same protein or polypeptides display different ascorbate oxidation abilities [ 40 , 44 ].…”

“…This changes the previous reduction model according to which Cu 2+ coordinated to the ATCUN binding site would first be reduced by ascorbate and the resulting Cu + would then be transferred to the His-His diade that is able to stabilize the reduced state of the metal ion [ 23 , 27 , 28 , 34 ]. Noteworthy is the fact that the literature data reveal that our model for the reduction of the Cu 2+ -Ctr1 (1-14) has been also suggested for HSA that contains an unspecific second metal binding domain [ 44 ]. This additional coordination site, characterized by an affinity to Cu 2+ lower than that of the Cu 2+ binding to the ATCUN motif of the protein, is thought to be responsible for ascorbate oxidation.…”

Incorporation of β‐Alanine in Cu(II) ATCUN Peptide Complexes Increases ROS Levels, DNA Cleavage and Antiproliferative Activity**

“…This activity increase due to Lys moieties has been reported before for Cu(II) Gly2À ATCUN complexes (corresponds to 1 vs. 2 in this work). [16,17,25] The Trp1/4 modification in 5 had a negative effect on the DNA cleavage activity (lane 8: 95 % form II). The β-Ala2 complexes 6 and 7 (Lys1/Trp4 and Trp1/Lys4) exhibited DNA cleavage properties to a similar extent (lanes 9 and 10: 85/60 % form III), with their activity placed between the less active complex 5 (Trp1/4) and complex 4 (Lys1/4).…”

Synthesis, Characterization, and Reaction Studies of Pd(II) Tripeptide Complexes

“…Strong ligating side chain moieties also serve as anchor groups; histidine is a well-studied example [ 19 , 20 , 21 ]. The so-called ATCUN-motif (Amino Terminal Cu and Ni) forms strong coordinating ligands with histidine as the third amino residue for the N-terminus (as seen in Figure 1 a).…”