Dengsen Zhu

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.

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.

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 β-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.

Roles of DMSO-type ruthenium complexes in disaggregation of prion neuropeptide PrP106–126

Ruthenium complexes are potential anticancer metallodrugs and inhibitors of various proteins, such as enzymes and even amyloid peptides. Studies on Aβ protein, human islet amyloid polypeptide, and prion neuropeptide have indicated that Ru complexes can inhibit amyloidosis. However, the interaction mechanism of peptides with Ru complexes remains unclear. In this study, we selected four dimethyl sulfoxide (DMSO)-type Ru complexes containing large aromatic ligands to explore and compare the interactions of Ru complexes with the prion neuropeptide PrP106–126. Results showed that, unlike new anti-tumor metastasis inhibitor-A-like compounds, these complexes can bind to PrP106–126 mainly through metal coordination and hydrophobic interaction. The Ru complexes disaggregated the PrP106–126 fibrils into scattered fragments or amorphous forms, thereby reducing the toxicity of PrP106–126. Among the four Ru complexes, complex 1, which consists of bipyridyl and DMSO ligands, exhibited the highest disaggregation ability and relatively high cell viability, which may be attributed to its molecular configuration and low cytotoxicity. These results suggested that Ru complexes are promising metallodrugs against amyloidosis-related diseases.

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.

Influence of oxodiperoxovanadate complexes on prion neuropeptide fibril formation

The neuropeptide PrP106–126 is used as a common model to study abnormal prion proteins. Some metal complexes are able to inhibit the formation of PrP106–126 fibrils and various compounds exhibit diverse interaction mechanisms. In this study, four oxodiperoxovanadate complexes were examined for inhibition of fibril formation of PrP106–126 and the mutant peptide M109F. Compounds 1, 3, and 4 directly interacted with the peptide and induced methionine oxidation. However, complex 2, which contains a large aromatic ligand, eliminated methionine oxidation activity and altered the inhibitory mechanism via steric effects. Aggregation was assessed by thioflavine T fluorescence and morphology analyses and complexes 1, 3, and 4 significantly decreased peptide fibril formation in comparison to 2. However, 2 caused increased cellular viability against amyloid peptide-induced cytotoxicity. This work elucidated the distinct role of a large aromatic ligand in peptide aggregation, binding affinity, and cytotoxicity.