A Water‐Soluble Peptoid that Can Extract Cu²⁺ from Metallothionein via Selective Recognition

Abstract

Selective binding of Cu 2 + in water medium by a synthetic chelatori sapromising therapeutic approacht owards the treatment of various diseases including cancer. Chelation of Cu 2 + is well exercised, however water-soluble synthetic chelators that can selectively bind Cu 2 + from a pool of competing metal ions at very high excess and/or can extract Cu 2 + from ap rotein are hardly reported. Herein we describe the design and synthesis of an acetylatedp eptoid-N-substituted glycine trimer-that incorporates ap icolyl group at the N-terminal, an on-coordinating but structurally directing bulky chiral phenylethyl group at the C-terminus and am odified 2,2'-bipyridine group (PCA-Nspe), which selectively binds Cu 2 + to form aw ater-soluble complex. We further demonstrate that the selectivity of PCA-Nspe to Cu 2 + is thermodynamically driven, leading to specific binding of Cu 2 + in an aqueous solution containing up to 60-fold excesso fo ther biologically relevant metal ions such as Zn 2 + ,C o 2 + ,M n 2 + ,C a 2 + ,M g 2 + ,K + and Na + .B ased on spectroscopic data and DFT calculations of PCA-Nspe as well as of ac ontrol peptoid having an achiral benzylg roup instead of the phenylethyls ide chain, we could suggest that the chiral and bulkierp henylethyl group at the C-terminus controlst he preorganization of the two ligands, and this might play arole in the selectivity of PCA-Nspe.Significantly, we show that PCA-Nspe can extract Cu 2 + from the natural copperbinding protein metallothionein. Scheme1.Acartoonrepresentation of Cu 2 + chelation from ac opper storage protein by as uitable chelator:apossible remedyf or Wilsond isease and cancer.

A Water‐Soluble Peptoid Chelator that Can Remove Cu2+ from Amyloid‐β Peptides and Stop the Formation of Reactive Oxygen Species Associated with Alzheimer's Disease

“…[16] Thus, it is desirable to develop a unique type of chelators, preferably peptidomimetic-based ones that can combine the advantages of both small molecules and peptide-based drug candidates. Peptoids [17] , N-Substituted glycine oligomers, are excellent candidates for the development of metal chelators as potential therapeutics for AD: they can be easily synthesized on a solid support by the submonomer approach, [18] which utilizes primary amines as building blocks and thus allows to introduce a variety of functional groups within the peptoid sequence, [19] they are able to fold into well-defined secondary structures in solution, [20] and could be employed in various biological activities including protein-protein interactions, [21] metal binding and recognition, [22] and catalysis. [23] Moreover, compared to peptides, peptoids exhibit high proteolytic resistance [24] and high membrane permeability, [16a] together with tolerance towards high salts concentration and various pH conditions.…”

A zinc (II) complex comprising an aminoethyl‐nitropyridine‐derived N,N,O‐donor Schiff base ligand serves as an efficient ON–OFF probe for Cu(II)

“…[6] Although Cu(II) is biologically relevant and its vitality is apparent from its effect as a co-factor in various metalloenzymes, plus its ability to show promising redox properties for DNA damage, overaccumulation of this ion generates biological, physiological, and environmental toxicity. [7][8][9][10] Various fluorescence sensors based on organic systems have been described in the published literature. [11][12][13][14][15] Reports on the use of luminescent metal complexes as sensors has shown improved results due to their different mechanisms, high selectivity, and precise binding sites.…”

Imaging of Al3+in plant roots by the interaction with a bisphenol A-based chemosensor

“…6) and considering H 2 O (COSMO) as the solvent using the Turbomole software package (V 7.3, OS: macOS Monterey). 31–34 The coordinates were obtained from previously reported crystal structures. 35,36 The corresponding Al 3+ complex of H 4 L was optimized with def2-SVP for non-metals and def2-TZVP for Al 3+ with the same solvent model at the DFT-D4 level.…”