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BINDING OF HEAVY METAL IONS TO AMYLOID-? PEPTIDES: INTERACTIONS WITH NAP PEPTIDES
Abstract
Neurodegenerative diseases are a group of pathologies that mainly affect neurons of the human brain. Particularly, Alzheimer disease (AD) is a neurodegenerative disorder, being manifested by neuronal and synaptic loss. One of the main pathological aspects of AD is aggregation of amyloid-? (A?) peptide. However, there are some neuropeptides that play an important role in immunity and neuroprotection. In addition, the presence of metal ions and their abnormal accumulation play a key role in this pathology. The interaction of A? peptides with metal ions produces a change in peptide conformation and leads to the occurrence of peptide-metal complexes. However, the molecular mechanism of A? neurotoxicity has not thoroughly been elucidated. Therefore, we focused on a particular neuroprotective peptide, called NAP, a small fragment derived from ADNP (activity-dependent neurotrophic protein), which is essential for a proper function of the brain. Here, we report the synthesis of some new structural analogs of both A?(9-16) peptide fragment and NAP peptide, which were investigated in the presence of copper and iron ions. Thus, in the native A?(9-16) sequence 9GYEVHHQK16, tyrosine (Tyr, Y10) and histidine (His, H13,14) residues were replaced with glycine (Gly). In parallel, serine (Ser, S5) residue was modified with glycine (Gly, G5) or histidine (His, H5) in the sequence of neuroprotective NAP peptide (1NAPVSIPQ8). All peptides were synthesized by Fmoc/t-butyl solid-phase synthesis (SPPS) and their structure as well as that of metal-peptide complexes was confirmed by MALDI-TOF mass spectrometry. Purification and separation of the peptides were performed by reverse phase high performance liquid chromatography (RP-HPLC).
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