Abstract
Amyloid fibrils are widely studied both as target in conformational disorders and as basis for the development of protein-based functional materials. The three Zr phthalocyanines bearing dehydroacetic acid residue (PcZr(L1)2) and its condensed derivatives (PcZr(L2)2 and PcZr(L3)2) as out-of-plane ligands were synthesized and their influence on insulin fibril formation was studied by amyloid-sensitive fluorescent dye based assay, scanning electron microscopy, fluorescent and absorption spectroscopies. The presence of Zr phthalocyanines was shown to modify the fibril formation. The morphology of fibrils formed in the presence of the Zr phthalocyanines differs from that of free insulin and depends on the structure of out-of-plane ligands. It is shown that free insulin mostly forms fibril clusters with the length of about 0.3–2.1 μm. The presence of Zr phthalocyanines leads to the formation of individual 0.4–2.8 μm-long fibrils with a reduced tendency to lateral aggregation and cluster formation (PcZr(L1)2), shorter 0.2–1.5 μm-long fibrils with the tendency to lateral aggregation without clusters (PcZr(L2)2), and fibril-like 0.2–1.0 μm-long structures (PcZr(L3)2). The strongest influence on fibrils morphology made by PcZr(L3)2 could be explained by the additional stacking of phenyl moiety of the ligand with aromatic amino acids in protein. The evidences of binding of studied Zr phthalocyanines to mature fibrils were shown by absorption spectroscopy (for PcZr(L1)2 and PcZr(L2)2) and fluorescent spectroscopy (for PcZr(L3)2). These complexes could be potentially used as external tools allowing the development of functional materials on protein fibrils basis.
Highlights
The formation and deposition of ordered filamentous protein aggregates known as amyloid fibrils are connected with a large number of human diseases, including amyloidoses and neurodegenerative disorders [1,2,3]
We have previously reported that the presence of macrocyclic metal complexes, namely out-of-plane coordinated phthalocyanines [37,38,39], planar phthalocyanines and porphyrazines [40] and tetraphenylporphyrins [41], are able to inhibit the fibril formation or significantly change the morphology of formed protein aggregates
It is known that the structural basis for the influence of phthalocyanines on amyloid fibrils aggregation relies on specific π−π interactions between the aromatic ring system of these molecules and aromatic residues in the amyloidogenic proteins [4, 56, 57]
Summary
The formation and deposition of ordered filamentous protein aggregates known as amyloid fibrils are connected with a large number of human diseases, including amyloidoses and neurodegenerative disorders [1,2,3]. Amyloid fibrils are highly ordered cross-β sheet protein aggregates widely studied as target against conformational disorders, but due to the high. Modification of insulin amyloid aggregation by functionalized Zr phthalocyanines study design, data collection and analysis, decision to publish, or preparation of the manuscript
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