Glucosyl Platinum(II) Complexes Inhibit Aggregation of the C-Terminal Region of the Aβ Peptide

Abstract

Neurodegenerative diseases are often caused by uncontrolled amyloid aggregation. Hence, many drug discovery processes are oriented to evaluate new compounds that are able to modulate self-recognition mechanisms. Herein, two related glycoconjugate pentacoordinate Pt­(II) complexes were analyzed in their capacity to affect the self-aggregation processes of two amyloidogenic fragments, Aβ21–40 and Aβ25–35, of the C-terminal region of the β-amyloid (Aβ) peptide, the major component of Alzheimerʼs disease (AD) neuronal plaques. The most water-soluble complex, 1Pt dep , is able to bind both fragments and to deeply influence the morphology of peptide aggregates. Thioflavin T (ThT) binding assays, electrospray ionization mass spectrometry (ESI-MS), and ultraviolet–visible (UV–vis) absorption spectroscopy indicated that 1Pt dep shows different kinetics and mechanisms of inhibition toward the two sequences and demonstrated that the peptide aggregation inhibition is associated with a direct coordinative bond of the compound metal center to the peptides. These data support the in vitro ability of pentacoordinate Pt­(II) complexes to inhibit the formation of amyloid aggregates and pave the way for the application of this class of compounds as potential neurotherapeutics.

Ruthenium(II)–Arene Complexes with Glycosylated NHC-Carbene Co-Ligands: Synthesis, Hydrolytic Behavior, and Binding to Biological Molecules

“…The presence of a sugar residue in the coordination sphere can also favor solubility in water and provide modulable chirality. Recently, our group extensively investigated glycoconjugation to improve the selectivity of organometallic platinum­(II/IV) − and gold­(I) , complexes. Notably, a Pt­(II) complex containing a glycoconjugated N- heterocyclic carbene ligand, [PtMe­(dmphen)­(ethene)­(NHC-glu)] + OTf (Figure ), was found to be extremely cytotoxic and selective to cancer cells with IC 50 values in the high nanomolar range.…”

Ruthenium complexes bearing glucosyl ligands are able to inhibit the amyloid aggregation of short histidine-peptides

“…[27][28][29][30] However, a five-coordinate trigonal bipyramidal glucoconjugate Pt(II) complex also was demonstrated to be an efficient inhibitor of β-amyloid fragments. 31 Noticeably, the decoration of organometallic compounds with bioactive moieties able to recognize specific targets is a valid strategy to increase the biological performance of the therapeutic agents. Glycoconjugation is one of the most successful approaches [32][33][34][35][36][37][38][39][40][41] because the presence of sugar residues can increase the selectivity through the Warburg effect, 42 the aqueous solubility, and their biocompatibility in general.…”

Metal Complexes as Promising Matrix Metalloproteinases Regulators

“…Besides the mentioned inhibitors above, metal complexes have been applied to reduce side effects and improve the selectivity of molecules to MMPs. Along with the multiple metal complexes that have anti-tumor ability targeting DNA/RNA or mitochondria and anti-Aβ aggregation ability to reduce the risk of onset and/or progression of cancers and AD [ 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ], various metal complexes (e.g., Pt-, Ru-, Fe-, Cu-, Au-, Ni-, Zn, Sn-complexes) could be applied as regulators for both expression and enzymatic activity of MMPs. Those metal complexes could be applied as cancer and AD treatments later.…”