Structure relationship of metalloporphyrins in inhibiting the aggregation of hIAPP.

Metalloporphyrins (FeTBAP, MnTBAP, FeTMPyP and MnTMPyP) have been proposed as effective therapeutic agents in ONOO-related disease including type 2 diabetes (T2D). As these metalloporphyrins share the structural similarities of the planar aromatic conjugation with a valuable class of inhibitors against amyloids fibrillation, they might be effective inhibitors via aromatic π-π stacking interactions with amyloid peptides. Here, we found that the anionic metalloporphyrins (FeTBAP and MnTBAP) are effective inhibitors against hIAPP fibrillation, while, the cationic metalloporphyrins (FeTMPyP and MnTMPyP) only have limited inhibitory effects. Besides, the porphyrin with iron center is more effective than the one with manganese center. Our results favor the electrostatic attraction contributes the main reason to the inhibitory effect between the anionic porphyrins and hIAPP, followed by the π-π stacking interactions between aromatic ring of porphyrins and hIAPP and the stronger coordination ability of iron center to hIAPP. Additionally, by comparison with FeTBAP, which can completely inhibit cytotoxicity induced by hIAPP via stabilizing hIAPP monomers, MnTBAP fails to reverse the cytotoxicity due to that it can only delay the transition of hIAPP from α-helix to β-sheet rich oligomers. Our results provide theoretical significance for further designing or screening of metalloporphyrins as bifunctional antidiabetic drugs.