Effect Of Metalloporphyrins On The Aggregation Of Amyloid Beta Peptide

The accumulation of amyloid-β（Aβ）peptides is one of the pathological hallmarks of Alzheimer’s disease（AD）.The results showed that oligomers and fibrils of Aβcould be cytotoxicity.In addition,some researches also confirmed that ONOO^-participated in the occurrence and development of AD.Therefore,the bifunctional inhibitors,which can not only inhibit the aggregation of Aβ,but also scavenge ONOO^-,have greater potential to be drugs for the treatment of AD.In recent years,more and more researchers are interested in some metal complexes as inhibitors of amyloid aggregation.A great number of studies have confirmed that hemin can inhibit the aggregation of Aβ.However,hemin can catalyze the production of reactive oxygen species,which limits its application as an AD inhibitor.Unlike hemin,heme derivatives（Fe TMPy P and Fe TBAP）are non-cytotoxic and highly effective ONOO^-scavengers.Therefore,they are widely used in the treatment of inflammatory diseases.In addition,some manganese porphyrins（Mn TMPy P and Mn TBAP）have attracted more attention in recent years due to their high efficiency in scavenging ONOO^-and better biological safety than iron porphyrins.Therefore,the four metalloporphyrins（Fe TMPy P,Mn TMPy P,Fe TBAP,Mn TBAP）,including two coordination centers(Fe³⁺and Mn³⁺)and two ligands（TMPy P and TBAP）were selected in this paper.The inhibitory effects of them on Aβaggregation were studied by fluorescence probes,confocal fluorescence microscope,transmission electron microscopy,circular dichroism spectroscopy,and ¹H NMR,etc.The results have been achieved as follows:（1）By comparing the inhibitory effect of metalloporphyrins on Aβaggregation,it was found that all of these porphyrins had certain inhibitory effects with different inhibitory abilities.When the metal centers are the same,the inhibitory effect of TMPy P was stronger than that of TBAP;when the ligands are the same,the inhibitory effect of Fe center porphyrin was stronger than that of Mn center porphyrin.（2）It was found that these porphyrins had a certain inhibitory ability through the study of the molecular mechanism of metalloporphyrins to inhibit Aβaggregation.The reason is that porphyrins are of large ring plane structure,which can compete with aromatic amino acids throughπ-πstacking action.Therefore,the porphyrins can block the interactions of inter/intra-peptide for achieving the purpose of inhibiting aggregation.The inhibitory effect of cationic ligand（TMPy P）metalloporphyrins were stronger than that of anionic ligand（TBAP）metalloporphyrins.The well inhibitory effect may be related to the stronger binding effect between TMPy P and histidine（His）,phenylalanine（Phe）and tyrosine（Tyr）of Aβ,which is related to the electrostatic interaction between TMPy P and Aβpeptide.Moreover,the binding force would be enhanced when the coordination center is Fe.