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

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, A beta(21-40) and A beta(25-35), of the C-terminal region of the beta-amyloid (A beta) peptide, the major component of Alzheimer's 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.

Automated summary

Two related pentacoordinate Pt(II) complexes were found to influence the self-aggregation processes of amyloidogenic fragments of beta-amyloid peptide, a major component of Alzheimer's disease neuronal plaques. The complexes were able to bind to the fragments and inhibit the formation of amyloid aggregates through direct coordinative bonding. These findings provide a theoretical basis for the potential application of these complexes as neurotherapeutics.