The pathogenesis of type 2 diabetes is associated with the formation of transient cytotoxic oligomers and the aggregation of islet amyloid polypeptide (IAPP) into fibrils. Inhibition of amyloid protein aggregation is known as a therapeutic strategy to treat protein misfolding diseases. Here, we tested the effect of diphenylpyrazole (DPP)-derived small molecule inhibitors on aggregation properties of hIAPP by utilizing the combination of isotope labeling and 2D IR spectroscopy. Thus, residue-specific structural information can be revealed during the kinetics of aggregation. We want to determine the effect of these inhibitors on the aggregation kinetic as well as structural changes. The effect of the inhibition on the FGAIL oligomer can be detected as well. Overall, the uncovered details in this study of small molecule inhibitors can help with a new drug target for oligomeric-specific inhibitions.

Elucidating the mechanism of inhibition of hIAPP via two dimensional infrared spectroscopy

ACS Fall 2021

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