Luminescent Metal-Chelating Pt(II) Complexes for Targeting Metal-Induced Protein Oligomerization

Protein misfolding diseases, including Alzheimer’s and Parkinson’s, arise when proteins fail to adopt their native conformations and instead form soluble aggregates known as amyloid fibrils. While early studies primarily focused on mature fibrils, recent research has shifted attention toward misfolded protein oligomers, which are now recognized as more toxic intermediates that play a central role in cellular dysfunction.[1] These oligomers impair cellular homeostasis through both loss-of-function mechanisms and toxic gain-of-function effects, making them critical targets for therapeutic intervention. Consequently, early detection of these species is essential for effective disease management; however, current diagnostic methods lack sufficient sensitivity and specificity to detect oligomers prior to fibril formation. Recent studies have highlighted the potential of luminescent Pt(II) complexes as molecular probes capable of both disrupting amyloid fibril formation and enabling the visualization of oligomeric species.[2] Additionally, certain monomeric proteins associated with pathology-related amyloidosis undergo oligomerization upon copper binding,[3] a process that ultimately promotes amyloid fibril formation. In this work, we present a family of Pt(II) complexes capable of interacting with amyloidogenic proteins while simultaneously capturing metal ions through a chelating moiety incorporated into the auxiliary ligand.