期刊
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
卷 167, 期 -, 页码 141-150出版社
ELSEVIER
DOI: 10.1016/j.ijbiomac.2020.11.161
关键词
Metalloporphyrin; Human islet amyloid polypeptide; Aggregation
资金
- National Natural Science Foundation of China [31770866, 32071282]
- Opening Fund of Hubei Key Laboratory of Bioinorganic Chemistry Materia Medica
Metalloporphyrins show potential as therapeutic agents for type 2 diabetes, with anionic metalloporphyrins such as FeTBAP and MnTBAP being effective inhibitors against hIAPP fibrillation. Iron center porphyrins are more effective than manganese center porphyrins in inhibiting hIAPP fibrillation.
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 pi-pi 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 p-p 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 alpha-helix to beta-sheet rich oligomers. Our results provide theoretical significance for further designing or screening of metalloporphyrins as bifunctional antidiabetic drugs. (C) 2020 Elsevier B.V. All rights reserved.
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