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Metal complexes can effectively inhibit the aggregation of amyloid peptides, such as Aβ, human islet amyloid polypeptide, and prion neuropeptide PrP106-126. Gold (Au) complexes exhibited better inhibition against PrP106-126 aggregation, particularly the Au-bipyridyl (bpy) complex; however, the role of different ligand configurations remains unclear. In the present study, three derivants of Au-bpy complexes, namely, [Au(Me2bpy)Cl2]Cl, [Au(t-Bu2bpy)Cl2]Cl, and [Au(Ph2bpy)Cl2]Cl, were investigated to determine their influence on the aggregation and disaggregation of PrP106-126. The steric and aromatic effects of the ligand resulted in enhanced binding affinity. Inhibition was significantly affected by a large ligand. The neurotoxicity of the SH-SY5Y cells induced by PrP106-126 was reduced by the three Au-bpy derivants. However, the disaggregation ability was not in accordance with the results obtained for selected complexes during inhibition, suggesting a different mechanism of interaction between gold complexes and PrP106-126. The key peptide residues contributed to both the inhibition and disaggregation capabilities through the metal coordination and the hydrophobic interaction with the metal complexes. Thus, understanding the aggregation mechanism of the prion peptide would be helpful in designing novel metal-based drugs against amyloid fibril formation.

Prion diseases belong to a group of infectious, fatal neurodegenerative disorders. The conformational conversion of a cellular prion protein (PrP(C)) into an abnormal misfolded isoform (PrP(Sc)) is the key event in prion disease pathology. PrP106-126 resembles PrP(Sc) in some physicochemical and biological characteristics, such as apoptosis induction in neurons, fibrillar formation, and mediation of the conversion of native cellular PrP(C) to PrP(Sc). Numerous studies have been conducted to explore the inhibiting methods on the aggregation and neurotoxicity of prion neuropeptide PrP106-126. We showed that PrP106-126 aggregation, as assessed by fluorescence assay and atomic force microscopy, is inhibited by platinum complexes cisplatin, carboplatin, and Pt(bpy)Cl2. ESI-MS and NMR assessments of PrP106-126 and its mutant peptides demonstrate that platinum complexes bind to the peptides in coordination and nonbonded interactions, which rely on the ligand properties and the peptide sequence. In peptides, methionine residue is preferred as a potent binding site over histidine residue for the studied platinum complexes, implying a typical thiophile characteristic of platinum. The neurotoxicity induced by PrP106-126 is better inhibited by Pt(bpy)Cl2 and cisplatin. Furthermore, the ligand configuration contributes to both the binding affinity and the inhibition of peptide aggregation. The pursuit of novel platinum candidates that selectively target prion neuropeptide is noteworthy for medicinal inorganic chemistry and chemical biology.

DMSO-type ruthenium complexes with aromatic ligands disaggregate the mature PrP106–126 fibrilsviametal coordination and hydrophobic interaction.

Neuroglobin, a member of vertebrate globin family, is distributed primarily in the brain and retina. Considerable evidence has accumulated regarding its unique ligand-binding properties, neural-specific distribution, distinct expression regulation, and possible roles in processes such as neuron protection and enzymatic metabolism. Structurally, neuroglobin enjoys unique features, such as bis-histidyl coordination to heme iron in the absence of exogenous ligand, heme orientational heterogeneity, and a heme sliding mechanism accompanying ligand binding. In the present work, molecular dynamics (MD) simulations were employed to reveal functional and structural information in three carboxyl murine neuroglobin mutants with single point mutations F106Y, F106L and F106I, respectively. The MD simulation indicates a remarkable proximal effect on detectable displacement of heme and a larger tunnel in the protein matrix. In addition, the mutation at F106 confers on the CD region a very sensitive mobility in all three model structures. The dynamic features of neuroglobin demonstrate rearrangement of the inner space and highly active loop regions in solution. These imply that the conserved residue at the G5 site plays a key role in the physiological function of this unusual protein.