Journal
JOURNAL OF INORGANIC BIOCHEMISTRY
Volume 197, Issue -, Pages -Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jinorgbio.2019.110721
Keywords
hIAPP; hIAPP19-37; hIAPP20-29; Aggregation; Oxidovanadium complexes; Inhibition
Funding
- National Natural Science Foundation of China [21473251, 21271185]
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Human islet amyloid polypeptide (hIAPP) is synthesized by pancreatic beta-cells and co-secreted with insulin. Misfolding and amyloidosis of hIAPP induce beta-cell dysfunction in type II diabetes mellitus. Numerous small organic molecules and metal complexes act as inhibitors against amyloid-related diseases, justifying the need to explore the inhibitory mechanism of these compounds. In this work, three oxidovanadium complexes, namely, (NH4)[VO(O-2)(2)(bipy)]center dot 4H(2)O (1) (bipy = 2,2' bipyridine), bis(ethyl-maltolato, O,O)oxido-vanadium(IV) (2), and (bipyH(2))H-2[O{VO(O-2)(bipy)}(2)]center dot 5H(2)O (3), were synthesized and used to inhibit the aggregation of hIAPP and its fragments, namely, hIAPP19-37 and hIAPP20-29. Results revealed that shortening the peptide sequence decreased the aggregation capability of hIAPP fragments, and the oxidovanadium complexes inhibited the fibrillization of hIAPP better than its fragments. Interestingly, the binding of oxidovanadium complexes to hIAPP and its fragments presented a distinct thermodynamic behavior. Oxidovanadium complexes featured the disaggregation capability against hIAPP, better than against its fragments. These complexes also decreased the cytotoxicity caused by hIAPP and its fragments by reducing the production of oligomers. 3 may be a good hIAPP inhibitor based on its inhibition, disaggregation capability, and regulatory effect on peptide-induced cytotoxicity. Oxidovanadium complexes exhibit potential as metallodrugs against amyloidosis-related diseases.
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