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Peroxynitrite scavenger FeTPPS effectively inhibits hIAPP aggregation and protects against amyloid induced
Pengfei Zhang1, Lizhen Zeng1, Wanxia Gao2
1Hubei Key Laboratory of Bioinorganic Chemistry & Materia Medica, School of Chemistry and Chemical Engineering, Huazhong University of Science & Technology, Wuhan 430074, PR China.
Abstract:
Type 2 diabetes (T2D) is associated with pancreatic β-cell dysfunction, which can be induced by oxidative stress or/and the aggregation of human islet amyloid polypeptide (hIAPP). Therefore, ONOO- and hIAPP become the crucial targets of T2D treatment. Previously, we found heme could be an effective inhibitor of hIAPP aggregation. However, heme causes serious toxic effects on cells, tissues and organs through oxidative stress, which block it as a potential drug candidate for T2D treatment. 5,10,15,20-tetrakis(4-sulfonatophenyl) porphyrinato iron(III) chloride (FeTPPS), a water-soluble derivative of heme, is recognized as a high-efficient ONOO- decomposition catalyst, which is reported to have a great therapeutic potential in ONOO- -related diseases, including T2D. Here, we explored the potentiality of FeTPPS to be an inhibitor of hIAPP aggregation and the protective effects on cytotoxicity of hIAPP aggregation. It was found that the interaction between FeTPPS and hIAPP remarkably affected hIAPP fibrillation by both stabilizing hIAPP monomers and disaggregating the long fibrils into small oligomeric species. Furthermore, unlike heme, the addition of FeTPPS completely reversed the cytotoxicity and ROS level induced by hIAPP, which was consistent with its strong inhibitory activity. These results implied that FeTPPS could be a promising agent for the treatment of T2D.
Insights
Iron(III) chloride (FeTPPS), a heme derivative, effectively inhibits human islet amyloid polypeptide (hIAPP) aggregation and reduces its toxicity, offering a promising therapeutic strategy for type 2 diabetes (T2D).
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Type 2 diabetes (T2D) is linked to pancreatic β-cell dysfunction, driven by oxidative stress and human islet amyloid polypeptide (hIAPP) aggregation.
- ONOO⁻ and hIAPP are key therapeutic targets for T2D.
- Heme inhibits hIAPP aggregation but exhibits toxicity; its derivative, FeTPPS, is a potent ONOO⁻ catalyst with therapeutic potential.
Purpose of the Study:
- To investigate the potential of FeTPPS as an inhibitor of hIAPP aggregation.
- To evaluate the protective effects of FeTPPS against hIAPP-induced cytotoxicity.
Main Methods:
- Investigated the interaction between FeTPPS and hIAPP.
- Assessed the impact of FeTPPS on hIAPP fibrillation kinetics and morphology.
- Evaluated FeTPPS's effect on hIAPP-induced cytotoxicity and reactive oxygen species (ROS) levels.
Main Results:
- FeTPPS interaction stabilized hIAPP monomers and disaggregated fibrils into smaller oligomers, inhibiting fibrillation.
- FeTPPS completely reversed cytotoxicity and reduced ROS levels induced by hIAPP.
- These effects correlated with FeTPPS's potent inhibitory activity against hIAPP aggregation.
Conclusions:
- FeTPPS demonstrates significant potential as a therapeutic agent for T2D by targeting hIAPP aggregation and associated toxicity.
- FeTPPS offers a safer alternative to heme, mitigating oxidative stress while inhibiting hIAPP-induced cellular damage.
