Inhibition Of Prion Amyloid Peptide Fibril Formation By Peroxovanadium Complexes

Protein conformational diseases mainly include Alzheimer’s disease, prion disease,Parkinson’s disease. The occurrence of neurodegenerative disease is related to aggregation of amyloid peptides, and normal type of protein conformation changes to pathogenic type. Prion protein conformational changes, deposition and neurotoxicity are closely related to the prion disease, and the pathogenic mechanism is that the normal prion protein Pr PC conversed to a pathogenic type protein PrPSc. In the work, we choose the N-terminal neuropeptide of prion protein PrP106-126. Physicochemical and biochemical properties of the N-terminal neuropeptide are similar to the pathogenic prion protein PrPSc, including fibrosis, cytotoxicity,anti-proteolytic activity and membrane permeability. In addition, methionine oxidation can significantly reduce amyloidfibril formation and proteinase K resistance, but it does not reduce the neurotoxicity of peptides in vivo and in vitro. Taking into account the above characteristics of residues Met, mutant peptide M109 F of prion neuropeptide PrP106-126 has been also used as the object of study, exploring inhibitors to resist amyloid peptide aggregation are used for the study of prion disease.In the paper, we chooses peroxovanadate vanadium complexes with variously steric effect and with analogous structure but diffrent ligands interact with Pr P106-126 and its mutant M109 F, and find these complexes have good inhibitory effect on two peptides and strong binding affinity. It is remarkable that the PrP106-126 NMR spectrum showed a significant influence on the resonance signals of His111 and Met109/112 after addition of vanadium complexes. Binding with mass spectrum, this suggested the methionine oxidation activity of the vanadium complexes and binding action between Pr P106-126 and its mutant M109 F and these complexes. In addition, the inhibitory ability of peroxovanadate vanadium complexes was not necessarily correlated with the binding affinity. Although some complexes exhibited better binding affinity, the inhibitory performance was not obvious. Inhibitoryeffects on Pr P106–126 might involve several factors, such as the configuration of V complexes, the binding ability of V complexes to monomers, oligomers and fibrils, as well as the physicochemical environment of the aggregated peptides. Although peroxovanadate vanadium complexes have certain cell toxicity in nerve cells by themselves, by interacting with PrP106-126 and its mutant M109 F, reducing cytotoxicity caused by the two peptide aggregates.Treatment of amyloid-related disease is a important challenge. In the research, we combing diverse experimental methods to study the interaction between amyloid peptide and peroxovanadate vanadium complexes. This work provides basic data for the investigation of potential metallodrugs against neurodegenerative disease.