SARAVANAN, Manikam S.; RYAZANOV, Sergey; LEONOV, Andrei; NICOLAI, Janine; PRAEST, Patrique; GIESE, Armin; WINTER, Roland; KHEMTEMOURIAN, Lucie; GRIESINGER, Christian; KILLIAN, J. Antoinette

doi:10.1038/s41598-019-54919-z

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SARAVANAN, Manikam S.

RYAZANOV, Sergey

LEONOV, Andrei

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Scientific Reports. 2019, vol. 9

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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 similar to 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 substoichiometric 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 nontoxic oligomers. Together, these results indicate that anle145c is a promising candidate for inhibition of amyloid formation in T2DM.< Réduire

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

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