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The small molecule inhibitor anle145c thermodynamically traps human islet amyloid peptide in the form of non-cytotoxic oligomers.

MPS-Authors
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Ryazanov,  S.
Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society;

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Leonov,  A.
Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society;

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Griesinger,  C.       
Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society;

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3182497_Suppl.pdf
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Citation

Saravanan, M. S., Ryazanov, S., Leonov, A., Nicolai, J., Praest, P., Giese, A., et al. (2019). The small molecule inhibitor anle145c thermodynamically traps human islet amyloid peptide in the form of non-cytotoxic oligomers. Scientific Reports, 9(1): 19023. doi:10.1038/s41598-019-54919-z.


Cite as: https://hdl.handle.net/21.11116/0000-0005-5D7B-A
Abstract
Type 2 diabetes (T2DM) is associated with aggregation of the human islet amyloid polypeptide (hIAPP) into cytotoxic amyloid species. Here we tested the effect of a diphenylpyrazole (DPP)-derived small molecule inhibitor, anle145c, on cytotoxicity and on aggregation properties of hIAPP. We demonstrate that incubation of hIAPP with the inhibitor yields ~10 nm-sized non-toxic oligomers, independent of the initial aggregation state of hIAPP. This suggests that anle145c has a special mode of action in which anle145c-stabilized oligomers act as a thermodynamic sink for the preferred aggregation state of hIAPP and anle145c. We also demonstrate that the inhibitor acts in a very efficient manner, with sub-stoichiometric concentrations of anle145c being sufficient to (i) inhibit hIAPP-induced death of INS-1E cells, (ii) prevent hIAPP fibril formation in solution, and (iii) convert preformed hIAPP fibrils into non-toxic oligomers. Together, these results indicate that anle145c is a promising candidate for inhibition of amyloid formation in T2DM.