Inhibition of amyloid peptide fibril formation by gold-sulfur complexes.

Amyloid-related diseases are characterized by protein conformational change and amyloid fibril deposition. Metal complexes are potential inhibitors of amyloidosis. Nitrogen-coordinated gold complexes have been used to disaggregate prion neuropeptide (PrP106-126) and human islet amyloid polypeptide (hIAPP). However, the roles of metal complexes in peptide fibril formation and related bioactivity require further exploration. In this work, we investigated the interactions of amyloid peptides PrP106-126 and hIAPP with two tetracoordinated gold-sulfur complexes, namely, dichloro diethyl dithiocarbamate gold complex and dichloro pyrrolidine dithiocarbamate gold complex. We also determined the effects of these complexes on peptide-induced cytotoxicity. Thioflavin T assay, morphological characterization, and particle size analysis indicated that the two gold-sulfur complexes effectively inhibited the fibrillation of the amyloid peptides, which led to the formation of nanoscale particles. The complexes reduced the cytotoxicity induced by the amyloid peptides. Intrinsic fluorescence, nuclear magnetic resonance, and mass spectrometry revealed that the complexes interacted with PrP106-126 and hIAPP via metal coordination and hydrophobic interaction, which improved the inhibition and binding of the two gold-sulfur compounds. Our study provided new insights into the use of tetracoordinated gold-sulfur complexes as drug candidates against protein conformational disorders.

Disaggregation of human islet amyloid polypeptide fibril formation by ruthenium polypyridyl complexes.

The toxicity of amyloid proteins is associated with many degenerative and systematic diseases. The aggregation of human islet amyloid polypeptide may induce pancreatic ß-cell death, which is linked to type II diabetes. Ruthenium complexes are inhibitors of various proteins and potential anticancer metallodrugs, which can also be used to disaggregate amyloid proteins. This work reported that several ruthenium polypyridyl complexes remarkably affected the peptide aggregation by predominant hydrophobic interaction and metal coordination, as reflected by thermodynamic parameters and mass spectrometry analysis. Morphology and particle size analysis showed that the amyloid fibrils were disaggregated from long fibrils into small nano particles. Addition of these complexes also decreased the cytotoxicity induced by the peptide. The results indicated that ruthenium polypyridyl complexes may be potential metallodrugs to treat amyloidosis.

Methionine oxidation of amyloid peptides by peroxovanadium complexes: inhibition of fibril formation through a distinct mechanism.

Fibril formation of amyloid peptides is linked to a number of pathological states. The prion protein (PrP) and amyloid-ß (Aß) are two remarkable examples that are correlated with prion disorders and Alzheimer's disease, respectively. Metal complexes, such as those formed by platinum and ruthenium compounds, can act as inhibitors against peptide aggregation primarily through metal coordination. This study revealed the inhibitory effect of two peroxovanadium complexes, (NH4)[VO(O2)2(bipy)]·4H2O (1) and (NH4)[VO(O2)2(phen)]·2H2O (2), on amyloid fibril formation of PrP106-126 and Aß1-42via site-specific oxidation of methionine residues, besides direct binding of the complexes with the peptides. Complexes 1 and 2 showed higher anti-amyloidogenic activity on PrP106-126 aggregation than on Aß1-42, though their regulation on the cytotoxicity induced by the two peptides could not be differentiated. The action efficacy may be attributed to the different molecular structures of the vanadium complex and the peptide sequence. Results reflected that methionine oxidation may be a crucial action mode in inhibiting amyloid fibril formation. This study offers a possible application value for peroxovanadium complexes against amyloid proteins.

Effects of gold complexes on the assembly behavior of human islet amyloid polypeptide.

Human islet amyloid polypeptide (hIAPP) is a well-known amyloid protein that is associated with type II diabetes. Inhibitors of this peptide include aromatic organic molecules, short peptides, and metal complexes, such as zinc, ruthenium and vanadium compounds. Various metal ions and their complexes affect the fibrillization of hIAPP in different action modes. However, the assembly mechanism of the peptide remains unclear. This study evaluated the inhibitory effects of three gold complexes with different nitrogen-containing aromatic ligands, namely, [Au(bipy)Cl2][PF6] (1), [Au(Ph2bpy)Cl2]Cl (2), and [Au(phen)Cl2]Cl (3), on the amyloid fibrillization of hIAPP. The complexes interacted with the peptide mainly through hydrophobic interaction and metal coordination. The concentration dependence of hIAPP aggregation on gold complex indicated that the assembly behavior of hIAPP is significantly affected by these compounds. The gold complexes inhibited peptide aggregation through dimerization and stabilized the peptide to monomers. Gold ion was found to be a key influencing factor of the binding mode and assembly behavior of hIAPP. The different effects of the complexes on peptide aggregation might be attributed to their special ligands. This study provided insights into the inhibitory mechanism of gold complexes against hIAPP fibrillization.

Inhibitory effects of NAMI-A-like ruthenium complexes on prion neuropeptide fibril formation.

Prion diseases are a group of infectious and fatal neurodegenerative disorders caused by the conformational conversion of a cellular prion protein (PrP) into its abnormal isoform PrP(Sc). PrP106-126 resembles PrP(Sc) in terms of physicochemical and biological characteristics and is used as a common model for the treatment of prion diseases. Inhibitory effects on fibril formation and neurotoxicity of the prion neuropeptide PrP106-126 have been investigated using metal complexes as potential inhibitors. Nevertheless, the binding mechanism between metal complexes and the peptide remains unclear. The present study is focused on the interaction of PrP106-126 with NAMI-A and NAMI-A-like ruthenium complexes, including KP418, KP1019, and KP1019-2. Results demonstrated that these ruthenium complexes could bind to PrP106-126 in a distinctive binding mode through electrostatic and hydrophobic interactions. NAMI-A-like ruthenium complexes can also effectively inhibit the aggregation and fibril formation of PrP106-126. The complex KP1019 demonstrated the optimal inhibitory ability upon peptide aggregation, and cytotoxicity because of its large aromatic ligand contribution. The studied complexes could also regulate the copper redox chemistry of PrP106-126 and effectually inhibit the formation of reactive oxygen species. Given these findings, ruthenium complexes with relatively low cellular toxicity may be used to develop potential pharmaceutical products against prion diseases.

Influence of gold-bipyridyl derivants on aggregation and disaggregation of the prion neuropeptide PrP106-126.

Metal complexes can effectively inhibit the aggregation of amyloid peptides, such as Aß, 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.

Regulation of aggregation behavior and neurotoxicity of prion neuropeptides by platinum complexes.

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.

Inhibition of human amylin fibril formation by insulin-mimetic vanadium complexes.

The toxicity of amyloid-forming proteins can be linked to many degenerative and systemic diseases. Human islet amyloid polypeptide (hIAPP, amylin) has been associated with type II diabetes. Methods for efficient inhibition of amyloid fibril formation are highly clinically important. This study demonstrated the significant inhibitory effects of six vanadium complexes on hIAPP aggregation. Vanadium complexes, such as bis(maltolato)-oxovanadium (BMOV), have been used as insulin-mimetic agents for the treatment of diabetes for many years. Different biophysical methods were applied to investigate the interaction between V complexes and hIAPP. The results indicated that the selected compounds affected the peptide aggregation by different action modes and protected the cells from the cytotoxicity induced by hIAPP. Both the high binding affinity and the ligand spatial effect on inhibiting hIAPP aggregation are significant. Although some of these compounds undergo biotransformation under the conditions of the experiments, and the active species are not identified, it is understood that the effect results from a particular compound and its conversion products. Importantly, our work provided information on the effects of the selected V complexes on hIAPP and demonstrated multiple levels of effects of V complexes against amyloid-related diseases.