Abstract
Misfolding and aggregation of the human islet amyloid polypeptide (hIAPP) are believed to play key roles in the pathophysiology of type-II diabetes. Here, we demonstrate that carbon dots (C-dots) prepared from the amino acid tyrosine inhibit fibrillation of hIAPP, reduce hIAPP-induced cell toxicity and block membrane disruption by the peptide. The pronounced inhibitory effect is traced to the display of ubiquitous aromatic residues upon the C-dots' surface, mimicking the anti-fibril and anti-toxic activity of natural polyphenolic compounds. Notably, spectroscopy and thermodynamics analysis demonstrated different hIAPP interactions and fibril inhibition effects induced by tyrosine-C-dots displaying phenolic residues and C-dots prepared from phenylalanine which exhibited phenyl units on their surface, underscoring the significance of hydrogen bonding mediated by the phenolic hydroxide moieties for the fibril modulation activity. The presented experiments attest to the potential of tyrosine-C-dots as a therapeutic vehicle for protein misfolding diseases, interfering in both π–π interactions as well as hydrogen bonding involving aromatic residues of amyloidogenic peptides.
Highlights
Protein misfolding and aggregation are the hallmarks of varied diseases and pathologies, including Alzheimer's disease (AD), Parkinson's disease (PD), and type 2 diabetes (T2D).[1]
The human islet amyloid polypeptide, a 37residue peptide secreted in the pancreatic b cells, has been identi ed as the main component of plaques found in the pancreas of diabetic patients.[2] hIAPP is intrinsically disordered,[3] undergoing a conformational change in which it adopts b-sheet structure between residues 8–19 and 25–37, further leading to bril formation.[4,5] hIAPP oligomers, are believed to be the main toxic species, likely through disruption of cell membranes.[6,7,8]
The experiments indicate a signi cant difference in hIAPP bril modulation activity between carbon dots (C-dots) prepared from tyrosine and C-dots synthesized from phenylalanine
Summary
Protein misfolding and aggregation are the hallmarks of varied diseases and pathologies, including Alzheimer's disease (AD), Parkinson's disease (PD), and type 2 diabetes (T2D).[1]. In light of the presumed closed relationship between hIAPP aggregation and its pathogenicity, inhibition of hIAPP selfassembly and bril formation have been a major strategy aimed at identifying therapeutic treatments to T2D.9. Synthetic aggregation inhibitors such as short peptides[9,10] metal nanoparticles[11,12,13] have been reported. Polyphenols, in particular, constitute a prominent family of aggregation inhibitors.[14,15] Curcumin and epigallocatechin gallate (EGCG), for example, inhibit aggregation and toxicity of hIAPP.[16,17] Resveratrol has been hypothesized to reduce toxicity of hIAPP by promoting
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